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Review

Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions

by
Rendy Hosea
1,2,
Sharon Hillary
1,2,
Shourong Wu
1,2,3,* and
Vivi Kasim
1,2,3,*
1
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
2
The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
3
Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China
*
Authors to whom correspondence should be addressed.
Cancers 2023, 15(13), 3506; https://doi.org/10.3390/cancers15133506
Submission received: 9 June 2023 / Revised: 28 June 2023 / Accepted: 3 July 2023 / Published: 5 July 2023
(This article belongs to the Special Issue Pleiotropic Pro-tumor Activities Regulated by Overexpressed Yin Yang 1 (YY1) in Human Cancers: Clinical Implications)
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Abstract

:

Simple Summary

Cancer is a global health problem with severe consequences. Certain genes, known as transcription factors (TFs), are overactive in many tumors. Targeting these TFs could be an effective approach to combat cancer. One such TF is called yin yang 1 (YY1) and plays important roles in tumor development. In preclinical studies, inhibiting YY1 has shown promise in slowing tumor growth, promoting cell death, and increasing the effectiveness of chemotherapy. Recent research suggests that combining YY1 inhibition with immunotherapy may enhance the effectiveness of treatment. However, there are challenges in developing drugs that specifically target YY1 and delivering them into the tumor. This review explores YY1 biology, its role in cancer, and various strategies for targeting YY1, including small molecule inhibitors, RNA interference, and gene editing techniques. The findings highlight the clinical implications of YY1-targeted therapy and the potential for novel therapeutic approaches that can improve patient outcomes.

Abstract

Cancer represents a significant and persistent global health burden, with its impact underscored by its prevalence and devastating consequences. Whereas numerous oncogenes could contribute to cancer development, a group of transcription factors (TFs) are overactive in the majority of tumors. Targeting these TFs may also combat the downstream oncogenes activated by the TFs, making them attractive potential targets for effective antitumor therapeutic strategy. One such TF is yin yang 1 (YY1), which plays crucial roles in the development and progression of various tumors. In preclinical studies, YY1 inhibition has shown efficacy in inhibiting tumor growth, promoting apoptosis, and sensitizing tumor cells to chemotherapy. Recent studies have also revealed the potential of combining YY1 inhibition with immunotherapy for enhanced antitumor effects. However, clinical translation of YY1-targeted therapy still faces challenges in drug specificity and delivery. This review provides an overview of YY1 biology, its role in tumor development and progression, as well as the strategies explored for YY1-targeted therapy, with a focus on their clinical implications, including those using small molecule inhibitors, RNA interference, and gene editing techniques. Finally, we discuss the challenges and current limitations of targeting YY1 and the need for further research in this area.

Graphical Abstract

1. Introduction

Cancer is a pervasive and deadly disease, claiming nearly 10 million lives annually [1]. Despite significant progress in treatment options such as chemotherapy, radiation therapy, and targeted therapies, cancer remains a significant public health challenge with high morbidity and mortality rates [2,3]. Tumor development is driven by aberrant gene expression, leading to dysregulation of the signal transduction pathways that promote oncogenic growth. Although there have been improvements in the survival rates for certain types of cancer, others remain difficult to treat and have a poor prognosis. Consequently, there is an urgent need for novel therapeutic approaches that can improve patient outcomes [4]. Transcription factors (TFs) are key regulators of gene expression, and their dysregulation can affect multiple hallmarks of cancer. By modulating the activity of oncogenic signal transduction pathways and regulating tumor gene expression, TFs play a crucial role in tumor progression [5] as they are involved in many aspects of tumors, including oncogenic signal transduction, cell death resistance, and drug resistance. Targeting TFs, therefore, represents a promising antitumor therapeutic strategy that could modulate a broader range of tumor properties and thus achieve a more robust and sustained therapeutic response in contrast to the typically limited effects observed in various kinase inhibitors, which primarily only block specific signaling pathways in tumor cells such as epidermal growth factor receptor (EGFR) inhibitor, Bcr-Abl inhibitor, and receptor tyrosine-protein kinase erbB-2 (HER2) inhibitor. Notably, clinical agents that target nuclear hormone receptors, a class of transcription factors that are activated by binding to a specific hormone and are then translocated to the nucleus to perform their transcription factor activity, have shown promising results in tumor treatment [6,7,8].
YY1 is a multifunctional transcription factor that plays a critical role in regulating the expression of the genes involved in various physiological processes, including development, cell proliferation, differentiation, DNA repair, and apoptosis [9,10,11,12,13,14]. Formerly known as NF-E1, YY1 was named for its dual activity as both a transcriptional activator and repressor [15]. YY1 has attracted attention as a target for antitumor therapy due to its aberrant expression in various tumors and its wide range of target genes; this range is predicted to occupy approximately 7% of mammalian genes [16]. Furthermore, in addition to its role as a traditional DNA-binding transcription factor, YY1 interacts with chromatin modifications through 3D chromatin organization to regulate cellular mechanisms more broadly [17]. YY1 modulates a mounting list of genes in different signaling pathways that regulate tumor development and progression, such as c-myc, c-fos, HER2, E1A, and p53 [18,19], and is involved in regulating various hallmarks of cancer, including sustained proliferative signaling, evading of programmed cell death, and deregulated metabolism.
YY1 has emerged as a promising target for antitumor therapy in recent years due to its critical role in regulating various hallmarks of cancer, such as tumor cell proliferation, evading programmed cell death, deregulated metabolism, induction of angiogenesis, activation of invasion and metastasis, genome instability, and evading immune system [11,19,20,21], as well as in tumor cell drug resistance [22,23,24]. YY1 is upregulated in various human cancers, including breast, bladder, cervical, colon, esophageal, liver, brain, and gastric cancers, and there is increasing evidence suggesting that it has pro-tumor consequences (Table 1) [25,26,27,28,29,30,31,32]. Moreover, YY1 upregulation is associated with poor prognosis and aggressive tumor behavior, characterized by increased tumor growth, invasion, and metastasis [25,26]. Therefore, targeting YY1 has the potential to inhibit tumor progression and sensitize tumor cells to therapy.
As a target for antitumor therapy, several approaches have been explored to target YY1, including small molecule inhibitors, RNA interference, and gene editing techniques. Small molecule inhibitors that disrupt the interaction between YY1 and its DNA binding sites have shown promising results in preclinical studies by inhibiting tumor growth and metastasis in various types of cancer [33,75,76]. Knocking down YY1 using RNA interference has also demonstrated efficacy in inhibiting tumor growth and sensitizing tumor cells to chemotherapy [31,33]. In preclinical studies, YY1 knockdown promotes apoptosis, inhibits cell proliferation, and enhances the effectiveness of chemotherapy in tumor cells. These findings suggest that targeting YY1 could be a promising strategy for tumor therapy. Additionally, gene editing techniques, such as clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) 9 (CRISPR-Cas9), have shown promise in preclinical studies as a means of targeting YY1 for antitumor therapy. Preclinical studies on gene editing techniques have demonstrated promising results in inhibiting tumor growth and metastasis in various types of cancer, including breast cancer, prostate cancer, and liver cancer [77,78,79]. However, clinical data on YY1-targeted therapies are currently lacking and further research, including clinical trials, is needed to fully demonstrate the safety and efficacy of YY1-targeted therapies in tumor patients. Nevertheless, the emerging evidence for the role of YY1 in cancer highlights its potential as a potential target for future research [33,56].
In this review, we will explore the potential of YY1-targeted therapy as a novel approach for tumor treatment and provide an overview of the different strategies that have been explored in preclinical and clinical studies.

2. The Roles of YY1 in Tumor Development and Progression

2.1. YY1 and Hallmarks of Cancer

Dysregulation of YY1 expression or function has been implicated in the pathogenesis of various types of cancer by influencing the hallmarks of cancer (Table 2) [19,20,80]. “The Hallmarks of Cancer” was originally proposed as a set of functional capabilities that human cells acquire during the transition from normal to neoplastic growth states [81,82,83]. These capabilities (e.g., sustaining proliferative signaling, insensitivity to growth-inhibitory signals, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis) are crucial for the formation of malignant tumors. Although this framework provides a solid foundation for understanding the biology of tumor cells, the original six hallmarks of cancer have since been updated to incorporate new developments that broaden the scope of cancer biology [81,82,83]. YY1 promotes tumor progression by regulating the expression of genes involved in cell proliferation and survival. YY1 activates the expression of oncogenes such as c-Myc, cyclin D1, and survivin and inhibits the expression of tumor suppressor genes such as p53 and p21 [61,84,85,86,87,88,89,90]. This leads to the dysregulation of the cell cycle and promotes the growth and survival of tumor cells [84,85,91,92,93].
YY1 can also promote angiogenesis, the formation of new blood vessels that supply nutrients and oxygen to tumors [84,103]. YY1 can stabilize hypoxia-inducible factor-1α (HIF-1α), thereby preventing its ubiquitination/proteasomal degradation and promoting transcription of the angiogenic factors vascular endothelial growth factor (VEGF) and transforming growth factor alpha (TGF-α) [84]. Furthermore, YY1 also promotes tumor angiogenesis by activating the transcription of VEGF while suppressing anti-angiogenic factors such as thrombospondin-1 (TSP-1), pigment epithelium-derived factor (PEDF), and tissue inhibitor of metalloproteinase 2 (TIMP-2) [103,133,134]. This leads to the formation of a network of blood vessels, thus supporting tumor growth and metastasis.
In addition, YY1 can promote tumor cell invasion and metastasis by regulating expression of the genes involved in cell adhesion and migration [135]. YY1 activates the expression of matrix metalloproteinases (MMPs) (enzymes that degrade the extracellular matrix), facilitating the remodeling of the surrounding tissue and creating the path for tumor cell migration. Simultaneously, YY1 inhibits the expression of E-cadherin, a protein crucial for cell–cell adhesion, further enabling tumor cell migration [43,110]. For instance, a study using gastric cancer cells showed that YY1 directly targets the MMP-14 promoter and enhances its transcriptional activity. MMP-14 plays a crucial role in cell invasion; hence, when YY1-induced MMP-14 expression is suppressed by miR-584-3p through methylation of the YY1 binding site in the MMP-14 promoter, the tumorigenesis and aggressiveness of gastric cancer cells were suppressed [43]. In addition, YY1 could promote epithelial–mesenchymal transition (EMT), the process at the initial stage of metastasis that is characterized by the loss of epithelial cell characteristics, including cellular polarity, cell-cell adhesion, and apical–basal polarity, as well as the acquisition of mesenchymal cell characteristics, such as increased migratory capacity, altered cytoskeletal organization, and enhanced extracellular matrix (ECM) remodeling [136,137]. EMT is characterized by the downregulation of genes that maintain the epithelial phenotype, such as E-cadherin, and the upregulation of genes that confer a mesenchymal phenotype, such as Twist1, Snail, and Vimentin [137]. YY1 activates the transcription of Snail and Vimentin by binding to their enhancer and promoter regions, respectively [55,138]. It also indirectly upregulates Twist1 by suppressing its inhibitor, heterogeneous nuclear ribonucleoprotein M (hnRNPM) [118]. Meanwhile, YY1 suppresses E-cadherin transcription by recruiting (protein arginine methyltransferase 7) PRMT7 to the proximal promoter of E-cadherin.
YY1 also suppresses the expression of genes involved in the immune response [139,140,141] and promotes immune evasion in tumor cells. Tumor cells may evade the host’s immune system through chronic inflammation, which inhibits and suppresses the function of effector immune cells, leading to tumor-promoting effects rather than tumor immunosurveillance. Additionally, tumor cells can create defects in antigen presentation mechanisms or upregulate ligands that neutralize cytotoxic T-cells, thereby eluding the adaptive immune system [98,142]. YY1 also contributes to immune evasion by activating the expression of immune checkpoint molecules such as programmed death-ligand 1 (PD-L1), which inhibits the activation of T cells and promotes immune tolerance in tumor cells [22].

2.2. YY1 and Drug Resistance

Drug resistance is a significant obstacle in the clinical therapy of cancer. Although chemotherapy drugs remain one of the most effective treatments for many types of cancer, the development of drug resistance can lead to the reduced effectiveness of these drugs and an increased risk of disease progression or recurrence [143]. Unfortunately, drug resistance is a common occurrence in many types of cancer and can contribute to treatment failure and poor patient outcomes [144].
YY1 has been implicated in the development of drug resistance in tumor cells (Figure 1) [39,107,145]. It can activate the expression of multidrug resistance genes such as multidrug resistance protein 1 (MDR1) and multidrug-resistance-associated protein 1 (MRP1), which encode drug efflux pumps that remove chemotherapy drugs from tumor cells and reduce their effectiveness [51]. YY1 could also promote the survival of tumor cells in the presence of chemotherapy drugs by repressing anti-apoptotic genes such as Bcl2-interacting mediator of cell death (Bim) and increasing protein B-cell lymphoma-extra-large (BCL-xL) [57,96,104].
In addition, YY1 can regulate the expression of genes involved in DNA repair and cell survival in response to DNA damage [9,146]. YY1 activates the expression of breast cancer-associated gene 1 (BRCA1) and X-ray repair cross-complementing 1 (XRCC1), which repair DNA damage caused by chemotherapy drugs, thereby protecting tumor cells from apoptosis [90,147]. This leads to the development of drug resistance in tumor cells and reduces the effectiveness of chemotherapy drugs [90,147].
Emerging research has demonstrated that targeting YY1 may be a promising strategy to overcome drug resistance in antitumor therapy. Preclinical studies in prostate cancer cell lines have demonstrated that downregulating YY1 expression or inhibiting its activity can sensitize tumor cells to the chemotherapy drug cisplatin and enhance its effectiveness [148,149,150]. The combination treatment of cisplatin and DETA-NONOate reversed resistance and induced apoptosis in cisplatin-resistant prostate cancer cell lines. This chemosensitization occurred due to the inhibition of nuclear factor-kappa B (NF-κB), an upstream regulator of YY1, as well as the downregulation of downstream genes regulated by YY1, such as the anti-apoptotic genes Bcl-xL and XIAP [150]. In addition, some studies have suggested that YY1 inhibition may sensitize tumor cells to other therapies, such as radiation and immunotherapy [108,151,152]. Altogether, these findings highlight the importance of exploring novel approaches to overcome drug resistance in antitumor therapy.

2.3. YY1 and Cancer Stem Cells

Cancer stem cells (CSCs) are a subpopulation of tumor cells that have the ability to self-renew and differentiate into multiple cell types and are thought to be responsible for tumor initiation, progression, and recurrence [153,154]. Moreover, CSCs are closely linked to metastasis, drug resistance, recurrence, and poor prognosis, which contribute to the challenge of completely eliminating tumors [155]. YY1 has been implicated in the regulation of CSCs in several types of cancer [156]. High levels of YY1 expression in breast tumor samples have been reported to be associated with stem cell markers, such as Oct4, Sox2, and Nanog [156]. Additionally, overexpression of YY1 positively regulates the effect on the CSC phenotype by increasing various stemness traits, such as the expression of stem cell transcription factors, sphere-forming potential, the proportion of CD44+/CD24− cells, and the ability to form tumors in vivo [157].
Notably, YY1 represses the expression of miR-879-5p by interacting with its promoter sequence, thereby activating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways and, subsequently, maintaining the CSC phenotype [157]. In glioblastoma CSCs, YY1 mediates self-renewal through regulation of the SENP1/METTL3/MYC axis. YY1 transcriptionally upregulates sentrin/SUMO-specific protease 1 (SENP1) and enhances the methylase activity of methyltransferase-like 3 (METTL3), leading to increased N6-Methyladenosine (m6A)-modification levels in MYC mRNA, which promotes the self-renewal of glioblastoma stem cells (GSCs) [158]. These examples demonstrate that YY1 overexpression leads to the maintenance of the CSC population, promotes tumor growth, and contributes to the resistance to therapy. Furthermore, YY1 can also regulate the interaction between CSCs and their microenvironment by activating the expression of cytokines and chemokines that recruit immune cells and promote the formation of a pro-inflammatory microenvironment that supports CSC survival and tumor growth [22,159].
Given the key role of CSCs in tumor initiation, progression, and recurrence, the targeting of CSCs has emerged as a promising therapeutic strategy for antitumor treatment. Many clinical trials targeting CSCs have been performed and show a promising future for antitumor therapy [155]. YY1 represents a potential therapeutic target in this context, given its key role in regulating CSCs in several types of cancer. For example, in brain CSCs, YY1 upregulates the expression of small nucleolar RNA host gene 17 (SNHG17), which extends the half-life of catenin beta 1 (CTNNB1) by sponging its direct negative regulator, miR-506-3p [160]. The upregulation of YY1 and SNHG17 promotes the activation of the Wnt pathway, which is associated with both tumorigenesis and CSC phenotype. Significantly, the downregulation of SNHG17 inhibits tumor growth in vitro and in vivo [160]. Additionally, YY1 inhibits miR-879-5p expression by interacting with its promoter sequence. This leads to the activation of the downstream PI3K/AKT and ERK1/2 pathways, which promote stemness in breast cancer cells. However, the suppressive effect of the YY1/miR-873-5p axis on the stemness of breast cancer cells can be reversed by inhibiting the PI3K/AKT and ERK1/2 pathways [157]. Therefore, understanding the mechanisms underlying YY1-mediated CSC regulation may provide novel therapeutic opportunities for antitumor treatment.

2.4. Current Development of YY1 Inhibitors

2.4.1. Small Molecule Inhibitors of YY1

Small molecule drugs are chemical compounds that have the ability to interact with specific targets, such as proteins or DNA, and modify their function [161,162]. The advancement of modern molecular biology and the use of advanced technologies such as computer-aided drug design, structural biology, and combinatorial chemistry has facilitated the rapid development of small-molecule targeted drugs for antitumor therapy [161]. Currently, the FDA has granted approval to more than 89 small-molecule targeted drugs to treat different forms of cancer, and there are several thousand targeted agents undergoing clinical trials for antitumor therapy [8]. In comparison with macromolecule drugs such as monoclonal antibodies, polypeptides, antibody–drug conjugates, and nucleic acids, small-molecule targeted drugs offer several benefits in terms of their pharmacokinetic characteristics, affordability, patient adherence, and drug handling and transportation [161]. Small molecule drugs can target a wide range of proteins, including kinases, epigenetic regulatory proteins, DNA damage repair enzymes, and proteasomes [161]. Small molecule drugs have also attracted attention for antitumor therapeutic strategies targeting YY1. At present, there are several small molecule drugs that have been identified to influence YY1 protein activity either through direct or indirect inhibition [163].

2.4.2. Diethylenetriamine NONOate (DETA-NONOate)

Nitric oxide donors can sensitize tumor cells to chemotherapy by releasing nitric oxide, which can alter the activity of various proteins containing sulfhydryl groups and modulate their activity through S-nitrosylation, which involves the transfer of a nitric oxide moiety to the sulfhydryl group of a protein [148,149]. One small molecule that has been investigated for its potential as a YY1 inhibitor is DETA-NONOate, which was reported in both in vitro and in vivo studies to inhibit the activities of YY1 and Bcl-xL, two proteins that can help tumor cells resist chemotherapy [150,164]. Treating tumor cells with DETA-NONOate resulted in the S-nitrosylation of YY1, leading to the inhibition of its DNA binding activity. Consequently, the negative regulation of Fas by YY1 was inhibited, resulting in upregulated Fas expression and tumor cell sensitization to Fas-induced apoptosis [150]. Moreover, animal studies have also shown that treatment with DETA-NONOate in combination with cisplatin led to a significant reduction in the expression levels of YY1 and Bcl-xL in tumor tissues [76,150,164]. Therefore, nitric oxide donors such as DETA-NONOate have great potential as antitumor therapy that targets YY1 and can enhance the cytotoxicity of antitumor therapies that depend on Fas-induced apoptotic tumor cell death, such as cell-mediated immunotherapy and immune checkpoint inhibition [165,166].
Although DETA-NONOate is still in the early stages of clinical development, nitric-oxide-mediated chemosensitization has shown potential as an antitumor therapeutic strategy in several clinical studies [148]. One example is nitroglycerin, which has shown promising results in lung cancer patients when used in combination with cisplatin, leading to improved response rates and longer time to progression [167]. Similarly, a clinical trial using slow-releasing nitroglycerine patches in men with high levels of prostate-specific antigen (PSA) after primary therapy resulted in a prolonged PSA doubling time, suggesting that nitric-oxide-induced inhibition of hypoxia-mediated progression may play a role in the observed therapeutic effects (NCT01704274) [168]. As a nitric oxide donor, nitroglycerin could inhibit NF-κB through S-nitrosylation, which could consequently interfere with NF-κB binding to DNA [169,170]. Another nitric oxide donor, RRx-001, is also capable of inducing NO production under hypoxic conditions and has demonstrated synergistic tumor cell cytotoxicity with radiation therapy by inhibiting the IκB kinase (IKK) complex, the master kinase for NF-κB activation [171,172,173]. NF-κB is an upstream regulator of YY1; hence, although the effect of nitroglycerin on YY1 has not been tested, these previous studies have suggested the possibility of using nitric oxide donors for an antitumor therapeutic strategy targeting YY1. However, NO donors may cause systemic toxicities, such as cytokine release syndrome. Therefore, there is a need for the development of new NO donors with localized effects to prevent systemic effects.

2.4.3. Betulinic Acid

Betulinic acid, a triterpenoid derived naturally from tree bark extracts, possesses a wide range of pharmacologic properties, including antiviral, antibacterial, anti-inflammatory, antimalarial, and antitumor activities [174,175]. This compound causes significant growth inhibition of various tumors in animal models [175,176]. Its effectiveness as an antitumor drug can be attributed to its ability to induce mitochondrial toxicity and generate reactive oxygen species, leading to apoptosis in liver, bladder, and colon cancers. The efficacy of betulinic acid as an antitumor drug is attributed to its ability to induce mitochondrial toxicity and the production of reactive oxygen species, leading to apoptosis in liver, bladder, and colon cancers [177,178,179].
In one study, betulinic acid inhibited the growth of breast cancer cells through the downregulation of YY1 [75]. HER2 played a major role in the proliferation of breast cancer cells and was affected by betulinic acid treatment, resulting in decreased expression of HER2 and p-HER2, as well as downstream kinases such as mitogen-activated protein kinase (MAPK), p-MAPK, Akt, and p-Akt. It was demonstrated that the downregulation of HER2-regulated genes caused by betulinic acid is primarily attributed to the decreased expression of YY1, which acts as an upstream regulator of HER2 [180]. Furthermore, betulinic acid directly binds to cannabinoid receptors (CB) and disrupts the signaling pathway, leading to the disruption of the miR-27a repression of ZBTB10. This disruption, in turn, inhibits tumor growth in a xenograft model. Notably, ZBTB10 itself serves as a repressor of YY1. Thus, betulinic acid downregulates YY1 through a CB-dependent pathway and the miR-27a/ZBTB10 axis [75].
Furthermore, betulinic acid has also demonstrated the ability to inhibit tumor growth and inhibit lung metastases when used in combination with vincristine [181,182]. However, betulinic acid has more limited applications as an anti-cancer agent due to its poor solubility in aqueous media. To date, no clinical trials have been published evaluating the antitumor potential of betulin. Despite this limitation, betulin has a high potential for forming derivatives with better solubility and antitumor properties [183].

2.4.4. ADP Ribosylation Factor like GTPase 6 Interacting Protein 5 (ARL6IP5) Gene Activating Compound (JAC1)

ARL6IP5, also known as JWA, is a gene that has been associated with the drug JWA activating compound 1 (JAC1). JAC1 is an antitumor drug that inhibits the proliferation of triple-negative breast cancer (TNBC) cells through the JWA/p38 MAPK and YY1/HSF1/p-Akt signaling pathways [184,185]. JAC1 specifically binds to YY1, thereby relieving YY1-mediated ARL6IP5 transcriptional repression and increasing the expression of ARL6IP5 [184]. ARL6IP5 acts as a tumor suppressor gene in tumor cells and is associated with multiple functions, including angiogenesis, proliferation, apoptosis, metastasis, and resistance to chemotherapy [186,187,188]. Its downregulation in tumors is correlated with poor prognosis [184]. Treatment with JAC1 restores ARL6IP5 expression and induces G1 phase arrest and apoptosis in TNBC cells through the p38 MAPK signaling pathway. Furthermore, JAC1 not only promotes ubiquitination and degradation of YY1 but also disrupts the interaction between YY1 and heat shock factor 1 (HSF1), thus suppressing the oncogenic role of HSF1 in TNBC through the p-Akt signaling pathway [184]. Although further research and clinical trials are needed to fully understand the potential of JAC1 as an inhibitor of YY1, JAC1 could serve as a potential antitumor agent for YY1-overexpressed malignant tumors since YY1 is highly expressed in many cancers and regulates genes related to the cell cycle, cell death, and tumor metabolism.

2.4.5. Peptide-Based Inhibition

In the past decade, advances in bioinformatics and genomics have uncovered a new class of small peptides called micropeptides, which are encoded by non-coding RNAs (ncRNAs). These micropeptides, typically composed of fewer than 100 amino acids, have been reported to play important roles in fundamental biological processes in a variety of organisms and may offer novel therapeutic opportunities that remain underexplored [189,190].
Micropeptides are distinct from other small bioactive peptides, such as neuropeptides and peptide hormones, which are typically derived from mRNA and are often cleaved from larger precursor proteins. Instead, micropeptides are encoded by small open reading frames (sORFs) within ncRNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) [191,192]. Recent genomic studies have helped to identify and characterize many novel micropeptides, which were often misannotated or overlooked. Some of these micropeptides have been found to contribute to diverse regulatory roles in embryogenesis, myogenesis, inflammation, diseases, and cancer [189,190,193].
Micropeptides have emerged as important regulators of cellular functions, including those involved in tumor cells. One lncRNA-encoded micropeptide that has garnered recent attention is the YY1-blocking micropeptide (YY1BM), which is encoded by LINC00278 [194]. YY1BM specifically binds to the transcription factor YY1, blocking its interaction with the androgen receptor (AR) and leading to the downregulation of eukaryotic elongation factor 2 kinase (eEF2K) expression in tumor cells through the AR signaling pathway. This, in turn, induces apoptosis in esophageal squamous cell carcinoma (ESCC) cells, suggesting that YY1BM may have potential as an antitumor agent [194].
Recent studies have shown that low YY1BM expression is associated with reduced apoptosis in ESCC tumors and tissues and that YY1BM expression may be controlled by cigarette smoking in male ESCCs through the deletion of m6A modifications. These findings suggest that YY1BM may serve as a potential prognostic biomarker and therapeutic agent that specifically targets YY1 in tumors [194].
Besides micropeptides, synthetic peptides have been developed to disrupt YY1 oligomerization with oncoproteins such as enhancer of zeste homolog 2 (EZH2), mouse double minute 2 (MDM2), protein kinase B (AKT), and adenovirus early region 1A (E1A), an interaction critical for facilitating enhancer formation and subsequent gene expression. These peptides are designed based on the oncoprotein binding domain (OPB) sequence, a 26-amino-acid region between G201 and S226 of YY1 [195,196], and have shown promise in reducing the growth of xenograft tumors generated by TNBC cells by binding to either YY1 or EZH2 to disrupt the recruitment of EZH2 by YY1. This leads to reduced H3K27me3 at the phosphatase and tensin homolog pseudogene 1 (PTENP1) and its upregulation [197,198]. Micropeptides are still in early preclinical testing, and more research is needed to assess their clinical efficacy. Nevertheless, as shown by its specificity, targeting YY1 using micropeptides has great potential as an antitumor therapy, and these findings have attracted considerable attention in this field.

2.4.6. Antibody-Based Inhibition

Several antibody-based inhibitors that affect YY1 have also been reported, including rituximab and galiximab. These drugs exert their antitumor effects by downregulating YY1 expression indirectly, which is achieved through the inhibition of NF-κB activity. NF-κB, which was previously known as the upstream regulator of YY1, is also a transcription factor that regulates immune responses and cell survival, and its dysregulation has been implicated in several human diseases, including cancer [199,200].
Rituximab, an FDA-approved monoclonal antibody targeting CD20, a protein expressed on B cells, has been used for treating B-cell non-Hodgkin’s lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) as it induces apoptosis [201,202]. Besides activating the caspase-dependent pathway, rituximab can downregulate the expression of YY1, which is upregulated in B-NHL and associated with poor prognosis, and inhibit NF-κB activity [62,203]. Rituximab decreased the phosphorylation of NF-κB-inducing kinase, IκB kinase (IKK), and IκB-alpha (IKK-α), as well as reducing the DNA binding activity of NF-κB, resulting in YY1 downregulation [203]. Rituximab also inhibits the chemoresistance mediated by NF-κB/YY1 axis regulation of Bcl-xL expression, thereby enhancing the efficacy of other antitumor drugs such as fludarabine, cyclophosphamide, and bendamustine. Furthermore, rituximab sensitizes B-NHL cells to immune-mediated killing by inhibiting NF-κB-mediated Fas resistance via YY1 downregulation [108,204].
Galiximab, a chimeric monoclonal antibody that targets CD80 and is currently in phase II clinical trials for the treatment of follicular lymphoma [205], could also downregulate YY1 expression by inhibiting NF-κB, which resulted in the induction of apoptosis in tumor cells [206]. In preclinical studies, galiximab has been shown to enhance the activity of cisplatin in terms of tumor cell killing [206,207], indicating that the combination of galiximab and cisplatin could be a promising strategy for the treatment of lymphoma.

2.4.7. Nucleic-Acid-Based Inhibition

MicroRNAs (miRNAs) and lncRNAs are both non-coding RNA molecules that play a significant role in gene regulation by binding to the 3′ untranslated region (UTR) of messenger RNA (mRNA) and inhibiting its translation into a protein [208,209]. lncRNAs can regulate miRNA function by acting as competing endogenous RNA (ceRNA) to mediate miRNA sponging and alter expression levels and functions [209].
Recently, there has been increasing interest in using both miRNAs and lncRNAs as potential therapeutic agents for antitumor therapy [210]. One promising approach for miRNAs is to specifically target the transcription factor YY1. For example, miR-29a, which was previously reported to inhibit tumorigenicity in non-small cell lung cancer (NSCLC) by downregulating DNA methyltransferase (DNMT)3A and 3B, can suppress YY1 mRNA and protein expression levels in lung tumor cells, resulting in suppressed proliferation and migration [211]. Meanwhile, previous studies have revealed that miR-186 could downregulate YY1 expression in lung and prostate tumor cells through binding to complementary sequences at 3′ UTR region of YY1 mRNA, leading to decreased cell migration and invasion [212]. Several other miRNAs could also target YY1 in various cancer types, including miR-101, miR-181, miR-186, miR-193a-5p, miR-215, miR-218, miR-381, miR-544, miR-5590-3p, miR-635, miR-7, and miR-7-5p [40,74,95,211,212,213,214,215,216,217,218,219,220,221,222], demonstrating the potential of miRNAs in antitumor therapy strategies.
One example of the regulation mediated by lncRNA is nasopharyngeal carcinoma copy number amplified transcript-1 (NPCCAT1), which is overexpressed in nasopharyngeal cancer. NPCCAT1 interacts with the 5′-UTR of YY1 mRNA, increasing its translation and resulting in increased cell proliferation and migration [223]. Another example of the lncRNA regulation upon YY1 was reported in breast cancer. Expression of YY1 was indirectly increased by long intergenic non-protein coding RNA 958 (LINC00958), which was positively regulated by METTL3. LINC00958 functioned as a ceRNA to sponge miR-378-3p, a miRNA that targets YY1. Therefore, METTL3-mediated LINC00958 upregulation led to reduced miR-378-3p availability and increased YY1 expression that consequently enhanced tumorigenesis [224].
lncRNAs are druggable targets that can be modulated by antitumor agents. Furthermore, genetic tools such as small interfering RNA (siRNA) can be employed to regulate ncRNA expression in antitumor therapy [209]. The lncRNA–miRNA axis regulates cell death mechanisms such as apoptosis and autophagy in tumors [225,226]. Furthermore, the lncRNA–miRNA axis determines the sensitivity of tumor cells to various types of antitumor therapy including chemotherapy, radiotherapy, and immunotherapy [209].
Although promising results have been obtained from preclinical studies for both miRNA and lncRNA, there is currently no miRNA-based or lncRNA-based inhibitor targeting YY1 or YY1-regulating ncRNAs that has been developed for clinical trials. However, there are several nucleic-acid-based inhibitors that can selectively target miRNAs, such as antisense oligonucleotides (ASOs) and peptide nucleic acids (PNAs). ASOs can be designed to prevent the interaction of endogenous ncRNAs with their target genes by fully or partially complementing the non-coding RNA [227,228]. Similarly, PNAs could be used for recognizing RNA targets and inducing antitumor effects in vitro and in vivo. Nevertheless, various non-coding RNA (ncRNA)-based therapeutics for cancer are currently undergoing different phases of clinical trials [229]. For example, TargomiRs have undergone a phase 1 clinical trial (NCT02369198) to examine their tumor-suppressive effect as a second- and third-line treatment for patients with recurrent malignant pleural mesothelioma and non-small cell lung cancer [230]. Another ncRNA-based therapeutic, MRG106 (also known as cobomarsen), has been evaluated in a phase I clinical trial for patients with lymphoma and leukemia (NCT02580552) [231]. Furthermore, RNA therapeutics have received approval from the FDA and/or the European Medicines Agency for various diseases, including retinitis, hypercholesterolemia, muscular atrophy, amyloidosis, and hyperoxaluria [232].
There are several challenges to using ncRNAs to target YY1 in tumors. A major challenge is to selectively target YY1 while minimizing off-target effects. Another challenge is delivering ncRNAs to tumor cells. ncRNAs are rapidly degraded in the bloodstream and are not efficiently taken up by cells, so more efficient delivery systems are needed to specifically deliver ncRNAs to tumor cells [233,234].
One potential approach is to use such nanoparticle-based delivery systems that can protect ncRNAs from degradation and improve their uptake by cells [235]. However, these systems are still in development and their safety and efficacy need to be thoroughly evaluated. In addition, translation into clinical practice is a significant challenge as ncRNA-based therapies are still in the early stages of development and their safety and efficacy need to be examined further in clinical trials [236].

2.5. CRISPR/Cas9 Genome Editing of YY1

CRISPR/Cas9 genome editing is a revolutionary technology that allows precise and efficient manipulation of the genome. It involves using a guide RNA molecule to target a specific DNA sequence and the Cas9 protein to cleave the DNA at that site. This can lead to gene disruption, gene knockdown, or gene correction [77,78]. CRISPR/Cas9 offers several advantages over RNA-based drugs, such as higher precision, the ability to target multiple genes simultaneously, and the potential for long-lasting effects due to its ability to make permanent changes to the genome.
Recently a study by Xu et al. employed CRISPR/Cas9 to downregulate YY1 in prostate cancer [79]. YY1 directly binds to and activates phosphofructokinase (PFKP), a gene encoding a glycolytic rate-limiting enzyme that significantly promotes the Warburg effect [91,237,238]. The Warburg effect is essential for tumor cells to acquire the energy and metabolize the nutrients that enable synthesis of the macromolecular precursors necessary to support the malignant growth promoted by YY1 in advanced prostate cancer. Lowering YY1 expression reduces PFKP expression and tumor cell metabolism while inhibiting mitosis and promoting apoptosis of prostate cancer cells [79]. In vivo observations corroborate this finding, as xenograft tumors of YY1 knockdown cells proliferate at a significantly slower rate than controls [79]. Although more preclinical studies need to be performed before CRISPR/Cas9 can be used in clinical settings, this result suggests that targeting YY1 expression using CRISPR/Cas9 offers promising potential for antitumor therapy.

2.6. YY1 and Immunotherapy

Combination therapy has emerged as a promising strategy for antitumor therapy, particularly in the context of immunotherapy. Although immunotherapy has shown remarkable success in some patients, many patients do not respond or develop resistance to therapy [239]. Therefore, combination therapy involving immunotherapy and other targeted agents, such as YY1-targeted therapy, has the potential to improve response rates and overcome resistance.
YY1 plays a crucial role in regulating the immune response in tumors by controlling the expression of various genes involved in immune cell activation, differentiation, and function in a range of immune cells, such as T cells, B cells, natural killer cells, and dendritic cells [101,121,139,140,141,240]. In immunotherapy, T cell exhaustion is a phenomenon that affects CD8+ T cells, where prolonged antigen exposure renders the cells hyporesponsive and incapable of eliminating tumor cells. This phenomenon is commonly linked to poor clinical outcomes in patients with solid malignancies [241]. Persistent antigenic stimulation causes the T cells to become exhausted, and it was reported that persistent T cell activation upregulates YY1 and EZH2 to epigenetically silence interleukin 2 (IL-2), a cytokine that plays a critical role in the activation and proliferation of T cells [241]. Therefore, the inhibition of YY1 has the potential to prevent T cell exhaustion and enhance the efficacy of immunotherapy by promoting IL-2 production and T-cell activation.
YY1-targeted therapy has good potential to be combined with immunotherapy drugs, such as checkpoint inhibitors and CAR-T cells. Checkpoint inhibitors are drugs that block inhibitory receptors on T cells, allowing them to better recognize and attack tumor cells [242]. However, many patients do not respond or develop resistance to checkpoint inhibitors [243]. In a previous study, the dual inhibition of cyclooxygenase-2 (COX-2) and EGFR by melafolone led to the downregulation of PD-L1, transforming growth factor beta (TGF-β), VEGF, and the PI3K/AKT pathway, which decreased tumor cell proliferation and enhanced the proliferation of CD8+ T cells [244]. This effect was likely due to the inhibition of PD-L1 expression, and it improved the efficacy of checkpoint blockade therapy [244]. Since YY1 is a positive regulator of both COX-2 and EGFR [101,111], inhibiting YY1 may be a promising strategy for increasing the effectiveness of checkpoint inhibitors. Therefore, combining YY1-targeted therapy with checkpoint inhibitors may have a synergistic effect on immune activation and warrants further investigation.
CAR-T cell therapy is a type of immunotherapy that involves engineering T cells to express chimeric antigen receptors that can recognize specific antigens on tumor cells. Whereas this approach has been successful in some patients, others do not respond or develop resistance to treatment [245]. Combining YY1-targeted therapy with CAR-T cells may help overcome resistance and improve response rates. One factor that can contribute to resistance is the expression of PD-L1 on tumor cells or the tumor microenvironment, which can inhibit CAR-T cell activity as these cells express programmed cell death protein 1 (PD-1) [245]. To address this, blocking immune checkpoints such as PD-1 may enhance the efficacy of CAR-T cell therapy. Previous studies combining anti-PD1 antibodies with CAR-T cells have shown promising results in a subset of patients [246,247,248,249]. Inhibition of YY1, which is a regulator of PD-L1 expression, maybe a promising strategy to overcome resistance in CAR-T cell therapy and improve patient outcomes.
Overall, these studies suggest that combination therapies involving YY1-targeted therapy and immunotherapy drugs have the potential to improve response rates and overcome resistance in antitumor therapy. Although clinical trials on drugs that directly target YY1 are still limited, clinical trials of certain drugs that may be correlated with the modulation of YY1 expression in cancer provide a strong foundation for the further development of a direct YY1 inhibitor. The strategies for YY1 inhibition discussed in this review are summarized in Figure 2 and Table 3.

2.7. Other Regulatory Functions of YY1

Besides its well-known function as a transcription factor, YY1 has also been reported to have functions beyond transcription factor roles. One such role is the post-translational modification of p53 by facilitating the interaction between MDM2 and p53 [88]. YY1 overexpression stimulates p53 ubiquitination and degradation. Conversely, YY1 silencing results in p53 accumulation due to a reduction in p53 ubiquitination and leads to increased tumor cell apoptosis. Furthermore, YY1 plays a role in stabilizing HIF-1α in response to hypoxic stress. Knockdown of YY1 can reduce the accumulation of HIF-1α and its activity under hypoxic conditions, consequently downregulating the expression of HIF-1α target genes in p53-independent manner. This resulted in suppression of tumor cell proliferation and angiogenesis potential [84]. Additionally, epigenetic regulation is a hallmark of cancer and YY1 has been implicated in the epigenetic regulation of various genes involved in tumorigenesis [250]. Epigenetic modifications play a critical role in cancer development and progression by regulating gene expression without altering the underlying DNA sequence [250]. These modifications involve various mechanisms such as DNA methylation, histone modifications, and chromatin remodeling [250]. YY1 interacts with multiple chromatin modifiers, including the Polycomb complex [251,252], histone deacetylases (HDACs) [253], histone acetyltransferases (HATs) [254], and protein arginine N-methyltransferase 1 (PRMT1) [255]. These interactions allow YY1 to regulate gene expression through histone modifications. YY1 also interacts with chromatin remodeling complexes such as the INO80 complex and the BAF complex [9,256,257]. These interactions facilitate access of YY1 to target genes and enhance its binding to and regulation of those genes. In addition to its role in chromatin modification and remodeling, YY1 also plays a role in three-dimensional (3D) chromatin organization [258]. YY1 interacts with the proteins involved in chromatin organization such as CCCTC-Binding Factor (CTCF) and cohesion [259,260]. These interactions allow YY1 to regulate DNA loop formation within CTCF–CTCF domains. Together, these findings highlight the diverse roles that YY1 plays in cancer biology, from post-translational modification to epigenetic regulation. Therefore, YY1’s role in cancer has attracted significant interest and continues to be an active area of investigation.
Table
Table 3. Summary of YY1 inhibitors and the results.
Table 3. Summary of YY1 inhibitors and the results.
Result
YY1 InhibitorsIn VitroIn Vivo
DETA-NONOateIncreased Fas-induced apoptosis [150]Downregulated Bcl-xL expression in mice bearing PC-3 tumor xenograft [76]
Sensitized cells to TRAIL-induced apoptosis in prostate cancer cell line (DU145, PC-3, CL-1, and LNCaP) [150]Inhibited tumor growth [76]
RRx-001Enhanced sensitivity to radiotherapy in HT29 and SCCVII cell lines [171]Enhanced sensitivity to radiotherapy in mouse model [171]
RRx-001 already passed phase I clinical trial. RRx-001 was well tolerated, with no notable toxicities nor adverse effects (NCT01359982)
RRx-001 is currently in a phase 2 clinical trial [171,172,173]
Inhibited Ikβ kinase complex [172,173]Inhibited Iκβ kinase complex [172,173]
Betulinic acidDownregulated YY1 in MDA-MB-453 cell line [75]Downregulated YY1 in BT474 xenografted nude mice [75]
Downregulated YY1-dependent HER2 expression in the MDA-MB-453 cell line [75]Decreased tumor growth [75]
Induced cell cycle arrest in G2/M phase [181]Decreased β2-microglobulin mRNA [181]
Decreased cell proliferation [180,181]Inhibited tumor growth and metastases [181,182]
JAC1Upregulated expression of ARL6IP5 [186,188]Inhibited formation of neo-vessels in gastric-cancer-bearing nude mice [188]
Downregulated HER2 expression [186]Inhibited angiogenesis of melanoma [188]
Reduced cell migration [186]
YY1BM (LINC00278)Downregulated eEF2K; induced apoptosis of ESCC cells [194]Increased apoptosis [194]
Synthetic peptides (YPB and OPB)Disrupted YY1-EZH2 [197]Inhibited tumor growth in xenograft of MDA-MB-231 cells [197]
Reduced H3K27me3 [197]
Upregulated PTENP1 and PTEN expression [197]
Inhibited cell proliferation of TNBC cell lines (MDA-MB-231 and MDA-MB-453) [197]
Reduced viability, reduced cell migration, in MDA-MB-231 [197]
RituximabInhibited NF-κB and Bcl-xL activity [108,203]Increased tumor regression [108]
Increased chemotherapy drug sensitivity [108,203]
Sensitized cells to immune-mediated killing [108,204]
GaliximabInhibited NF-κB activity [207]Chemosensitized malignant B cells [207]
Reduced proliferation of B-NHL cell lines [207]Galiximab already passed phase I/II clinical trial, result indicates that galiximab can be safely used.
Galiximab is currently in phase III clinical trials [207]
Sensitized resistant B cells to chemotherapy and immunotherapy [207]
Induced malignant B cell apoptosis [207]
miR-29aDownregulated DNMT 3A and 3B in A549 cells [211]
Suppressed cell proliferation and migration in A549 cells [211]
Inhibited IL-13-induced YY1 in A549 cells [211]
Inhibited tumorigenicity in A549 cells [211]
Decreased cell migration and invasion of A549 cells [211]
miR-186Inhibited proliferation, invasion, and migration of A549 and HCC827 cells [212]
Induced apoptosis of A549 and HCC827 cells [212]
miR-181Reduced cell proliferation of HeLa, HeLa-229, SiHa, and C33 cells [213]Suppressed tumor growth in nude mice with HeLa cells [213]
Increased cell apoptosis of HeLa, HeLa-229, SiHa, and C33 cells [213]
miR-193a-5pDecreased cell proliferation and migration of HEC-1-A, HEC-1-B, AN3CA, RL95-2, and KLE [95]Inhibited development and progression of primary endometrioid endometrial adenocarcinoma [95]
miR-215Suppressed cell proliferation, cell migration, and invasion in LS174T, LoVo, HT29, HCT116, SW480, and SW620 cells [214]
miR-218Inhibited cell proliferation of U251MG and 293T cells [220]
miR-381Inhibited cell proliferation, cell migration, and invasion of OVCAR3, Caov-3, OVCA429, SKOV3, A2780, and COV644 cells [217]
miR-544Decreased cell viability, proliferation, and migration of SW173 and 8350C [74]Suppressed tumorigenicity of ATC cells [74]
miR-5590-3pInhibited cell proliferation and migration of MDA-MB-436, MDA-MB-468, BT549, and MDA-MB-231 [219]Suppressed tumor growth xenograft mice model with BT549 cell [219]
miR-635Inhibited invasion of H522 and H1299 cells [218]Inhibited tumor growth in null mice with H522 cells [218]
miR-7Suppressed cell proliferation of HCT116, LoVo, and DLD-1 cells [40]Suppressed tumor growth in xenograft mice model [40]
Induced apoptosis of HCT116, LoVo, and DLD-1 cells [40]
miR-7-5pSensitized LN229 cells to temozolomide [222]Sensitized LN229 cells to chemotherapy drug temozolomide in nude mice [222]
Suppressed cell stemness of LN229 [222]
TargomiRs Already passed phase I
Clinical trial against malignant pleural mesothelioma and NSCLC (NCT02369198) [230]; the result indicated that TargomiRs were well tolerated in the first 5 patients and associated with transient cytokine-mediated reactions.
MRG106 (Cobomarsen) Cobomarsen already passed phase I clinical trial against lymphoma and leukemia (NCT02580552) [226]; the result indicated that cobomarsen was well tolerated, has potential clinical activity, and has the potential to improve the life quality of myelofibrosis patients.
CRISPR/Cas9Reduced glycolysis of HEK293 and HEK293T cells [79]Reduced cell proliferation in tumor xenograft of NOD/SCID/gamma null mice with 22Rv1 cells [79]
Increased apoptosis of HEK293 and HEK293T cells [79]

3. Conclusions

YY1-targeted therapies show promise as a novel approach to antitumor treatment; however, several challenges must be addressed before they can be translated into clinical settings. One of the challenges is the specificity of YY1-targeted therapies. Although small molecule drugs can decrease the expression of YY1, they may also affect other cellular processes, such as DNA replication and cell division, causing unintended consequences [161]. For example, studies investigating the effects of YY1 inhibition in tumor cells using a nitric oxide donor found that the drug not only inhibited YY1 expression but also caused cytokine release syndrome [148,261]. YY1 is a transcription factor that regulates the expression of many genes; targeting it may have unintended effects on normal cells and tissues. Therefore, it is essential to develop specific methods that can selectively target tumor cells while sparing normal cells. One potential approach is the use of antibody–drug conjugates (ADCs) for the selective delivery of YY1 inhibitors into tumor cells, thus minimizing the off-target effects on normal cells [262].
Moreover, another critical and fundamental problem is the high homology between YY1 and YY2, another member of the YY family of transcription factors [263]. YY1 and YY2 are highly homologous, with 56.2% similarity in their overall protein sequences and 86.4% similarity in the protein sequences within their zinc finger domains [264]. However, unlike YY1, which is upregulated in tumor tissues and is oncogenic, YY2 is downregulated in tumor tissues and is a tumor suppressor protein [93,263,265]. YY2 can trigger the ultraviolet damage response, p53-mediated cell cycle arrest, and tumor cell ferroptosis, thereby suppressing tumor growth [93,265,266]. Due to the high similarity in their nucleic acid and in amino acid sequences, designing drugs specifically targeting YY1 is challenging [264,267]. Furthermore, previous studies have reported the cross-reactivity of several antibodies targeting YY1 and YY2 [268]. These factors highlight the need for specific YY1 inhibitors that can selectively target YY1 without affecting YY2 to overcome the challenges posed by the homologous YY2 protein.
Furthermore, a cautionary note must be taken into account when developing and administering drugs targeting YY1. Although YY1 has oncogenic role in cancer, emerging reports suggest that it may also function as a tumor suppressor in certain cancer types [80]. The mechanism governing these opposing roles for YY1 is not yet fully understood. Therefore, it is crucial to consider the specific context of YY1 expression and activity to avoid unintentional adverse effects, such as the risk for secondary cancer. Careful assessment of the context-specific effects of YY1 modulation is necessary to ensure the safe and effective use of YY1-targeted therapies.
Another challenge is the efficacy of YY1-targeted therapies. Although they have shown promising results in preclinical studies, their efficacy in clinical settings may be limited by various factors, including drug resistance, the heterogeneity of tumor cells, and the tumor microenvironment [144]. To enhance their efficacies, developing combination therapies that target YY1 along with other pathways or drugs may be beneficial. Combination therapies can potentially overcome drug resistance, a major challenge in antitumor therapy, by targeting multiple pathways involved in tumor growth and progression [269]. For example, combining a YY1 inhibitor with an immunotherapy agent that targets the immune system’s response to tumors could enhance the immune system’s ability to recognize and destroy tumor cells, potentially improving patient survival [24,25].
Drug delivery to the tumor site is another challenge. The tumor microenvironment plays a crucial role in tumor progression and the treatment response and could impact the efficacy of YY1-targeted therapies in multiple ways [270,271]. For example, the presence of immune cells, such as T cells and myeloid-derived suppressor cells, can contribute to drug resistance by creating an immunosuppressive environment that shields tumor cells from the effects of treatment [270,271]. Moreover, the presence of stromal cells, such as cancer-associated fibroblasts, and extracellular matrix can hinder drug delivery to the tumor site by creating a physical barrier that prevents drugs from reaching the tumor cells [272]. Therefore, developing strategies to overcome these barriers and enhance drug delivery to the tumor site is essential to improve the efficacy of YY1-targeted therapies. Alternative drug delivery methods, such as nanoparticles or other drug delivery systems, have been explored to address this challenge [233,234,235]. These methods can improve drug delivery to the tumor site and potentially enhance therapeutic efficacy. For example, in a preclinical study, exosome-based nanoparticles could enhance the efficacy of delivering YY1 inhibitors into glioblastoma cells in both in vitro and in vivo models of the blood–brain barrier (BBB) [273]. Further research into alternative delivery methods for YY1-targeted therapies could offer new possibilities for antitumor therapy.
Finally, identifying biomarkers that can predict the response to treatment is a promising avenue for future research. Biomarkers, such as genetic mutations, epigenetic modifications, and protein expression patterns, have been reported to be associated with sensitivity or resistance to YY1-targeted therapies in preclinical studies [25]. By identifying patients who are most likely to respond to YY1-targeted therapies, personalized treatment plans can be developed to maximize therapeutic efficacy and minimize potential side effects [274]. Therefore, further research is needed to validate these biomarkers in clinical settings and to develop standardized tests for their detection, which can facilitate their use in routine clinical practice. It is also noteworthy that targeting YY1 binding partners, such as p300 and BRD4, can also lead to therapeutic effects that are similar to targeting the YY1 protein itself [79,88,89,275,276,277]. Further investigation into these alternative approaches could offer new possibilities for developing more effective YY1-targeted therapies.
Overall, YY1 has garnered extensive research interest for its role in gene regulation in tumor cells, exhibiting both activation and repression capabilities. Its involvement in various cancer hallmarks highlights its potential as a target for antitumor therapy. However, challenges remain in terms of drug specificity, efficacy, and delivery. To augment the success of YY1-targeted therapies, strategies such as combination therapies, alternative drug delivery methods, and the identification of treatment response biomarkers may be employed to improve the efficacy and clinical translation of YY1-targeted therapies. Nevertheless, targeting YY1 is a promising antitumor strategy, and the innovative approach mentioned in this review could lead to successful treatments and improved patient outcomes in the future (Figure 3).

Author Contributions

Conceptualization, V.K. and S.W.; investigation, R.H.; writing—original draft preparation, R.H. and S.H.; writing—review and editing, V.K. and S.W.; visualization, R.H. and S.H.; supervision, V.K. and S.W. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82173029, 32070715, and 32270778) and the Natural Science Foundation of Chongqing (CSTB2022NSCQ-MSX0611 and CSTB2022NSCQ-MSX0612).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Our intention is to summarize the state of the field. However, due to space limitations, we would like to apologize to authors whose works are not cited here. Their contributions should not be considered less important than those that are cited.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. Zhang, Y.; Zhang, Z. The history and advances in cancer immunotherapy: Understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell. Mol. Immunol. 2020, 17, 807–821. [Google Scholar] [CrossRef] [PubMed]
  3. Mellman, I.; Coukos, G.; Dranoff, G. Cancer immunotherapy comes of age. Nature 2011, 480, 480–489. [Google Scholar] [CrossRef] [Green Version]
  4. Soerjomataram, I.; Bray, F. Planning for tomorrow: Global cancer incidence and the role of prevention 2020–2070. Nat. Rev. Clin. Oncol. 2021, 18, 663–672. [Google Scholar] [CrossRef]
  5. Lee, T.I.; Young, R.A. Transcriptional regulation and its misregulation in disease. Cell 2013, 152, 1237–1251. [Google Scholar] [CrossRef] [Green Version]
  6. Darnell, J.E., Jr. Transcription factors as targets for cancer therapy. Nat. Rev. Cancer 2002, 2, 740–749. [Google Scholar] [CrossRef] [PubMed]
  7. Bushweller, J.H. Targeting transcription factors in cancer—From undruggable to reality. Nat. Rev. Cancer 2019, 19, 611–624. [Google Scholar] [CrossRef]
  8. Henley, M.J.; Koehler, A.N. Advances in targeting ‘undruggable’transcription factors with small molecules. Nat. Rev. Drug Discov. 2021, 20, 669–688. [Google Scholar] [CrossRef]
  9. Wu, S.; Shi, Y.; Mulligan, P.; Gay, F.; Landry, J.; Liu, H.; Lu, J.; Qi, H.H.; Wang, W.; Nickoloff, J.A.; et al. A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair. Nat. Struct. Mol. Biol. 2007, 14, 1165–1172. [Google Scholar] [CrossRef] [Green Version]
  10. Nicholson, S.; Whitehouse, H.; Naidoo, K.; Byers, R. Yin Yang 1 in Human Cancer. Crit. Rev. Oncog. 2011, 16, 245–260. [Google Scholar] [CrossRef]
  11. Deng, Z.; Cao, P.; Wan, M.M.; Sui, G. Yin Yang 1: A multifaceted protein beyond a transcription factor. Transcription 2010, 1, 81–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Dong, X.; Kwan, K.M. Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis. Mol. Brain 2020, 13, 104. [Google Scholar] [CrossRef] [PubMed]
  13. Varum, S.; Baggiolini, A.; Zurkirchen, L.; Atak, Z.K.; Cantù, C.; Marzorati, E.; Bossart, R.; Wouters, J.; Häusel, J.; Tuncer, E. Yin Yang 1 orchestrates a metabolic program required for both neural crest development and melanoma formation. Cell Stem Cell 2019, 24, 637–653.e9. [Google Scholar] [CrossRef] [Green Version]
  14. Zurkirchen, L.; Varum, S.; Giger, S.; Klug, A.; Häusel, J.; Bossart, R.; Zemke, M.; Cantù, C.; Atak, Z.K.; Zamboni, N. Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner. Nat. Commun. 2019, 10, 2192. [Google Scholar] [CrossRef] [Green Version]
  15. Shi, Y.; Seto, E.; Chang, L.-S.; Shenk, T. Transcriptional repression by YY1, a human GLI-Krüippel-related protein, and relief of repression by adenovirus E1A protein. Cell 1991, 67, 377–388. [Google Scholar] [CrossRef] [PubMed]
  16. Atchison, M.; Basu, A.; Zaprazna, K.; Papasani, M. Mechanisms of Yin Yang 1 in oncogenesis: The importance of indirect effects. Crit. Rev. Oncog. 2011, 16, 143–161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Weintraub, A.S.; Li, C.H.; Zamudio, A.V.; Sigova, A.A.; Hannett, N.M.; Day, D.S.; Abraham, B.J.; Cohen, M.A.; Nabet, B.; Buckley, D.L.; et al. YY1 Is a Structural Regulator of Enhancer-Promoter Loops. Cell 2017, 171, 1573–1588.e28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Sui, G. The regulation of YY1 in tumorigenesis and its targeting potential in cancer therapy. Mol. Cell. Pharmacol. 2009, 1, 157–176. [Google Scholar] [CrossRef] [Green Version]
  19. Gordon, S.; Akopyan, G.; Garban, H.; Bonavida, B. Transcription factor YY1: Structure, function, and therapeutic implications in cancer biology. Oncogene 2005, 25, 1125–1142. [Google Scholar] [CrossRef] [Green Version]
  20. Meliala, I.T.S.; Hosea, R.; Kasim, V.; Wu, S. The biological implications of Yin Yang 1 in the hallmarks of cancer. Theranostics 2020, 10, 4183–4200. [Google Scholar] [CrossRef]
  21. Cho, A.A.; Bonavida, B. Targeting the Overexpressed YY1 in Cancer Inhibits EMT and Metastasis. Crit. Rev. Oncog. 2017, 22, 49–61. [Google Scholar] [CrossRef] [Green Version]
  22. Hays, E.; Bonavida, B. YY1 regulates cancer cell immune resistance by modulating PD-L1 expression. Drug Resist. Updates 2019, 43, 10–28. [Google Scholar] [CrossRef]
  23. Matsumura, N.; Huang, Z.; Baba, T.; Lee, P.S.; Barnett, J.C.; Mori, S.; Chang, J.T.; Kuo, W.-L.; Gusberg, A.H.; Whitaker, R.S.; et al. Yin yang 1 modulates taxane response in epithelial ovarian cancer. Mol. Cancer Res. 2009, 7, 210–220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Kwiatkowska, D.; Mazur, E.; Reich, A. YY1 is a key player in melanoma immunotherapy/targeted treatment resistance. Front. Oncol. 2022, 12, 856963. [Google Scholar] [CrossRef]
  25. Fu, X.; Ji, F.; He, Q.; Qiu, X. A Systematic Pan-Cancer Analysis of YY1 Aberrations and their Relationship with Clinical Outcome, Tumor Microenvironment, and Therapeutic Targets. J. Immunol. Res. 2022, 2022, 5826741. [Google Scholar] [CrossRef] [PubMed]
  26. Zhang, Q.; Stovall, D.B.; Inoue, K.; Sui, G. The oncogenic role of Yin Yang 1. Crit. Rev. Oncog. 2011, 16, 163–197. [Google Scholar] [CrossRef]
  27. Bonavida, B.; Kaufhold, S. Prognostic significance of YY1 protein expression and mRNA levels by bioinformatics analysis in human cancers: A therapeutic target. Pharmacol. Ther. 2015, 150, 149–168. [Google Scholar] [CrossRef] [PubMed]
  28. Liu, N.; Steer, C.J.; Song, G. MicroRNA-206 enhances antitumor immunity by disrupting the communication between malignant hepatocytes and regulatory T cells in c-Myc mice. Hepatology 2022, 76, 32–47. [Google Scholar] [CrossRef]
  29. Bonavida, B.; Huerta-Yepez, S.; Baritaki, S.; Vega, M.I.; Liu, H.; Chen, H.; Berenson, J.R. Overexpression of Yin Yang 1 in the pathogenesis of human hematopoietic malignancies. Crit. Rev. Oncog. 2011, 16, 261–267. [Google Scholar] [CrossRef]
  30. Tsang, D.P.F.; Wu, W.K.K.; Kang, W.; Lee, Y.-Y.; Wu, F.; Yu, Z.; Xiong, L.; Chan, A.W.; Tong, J.H.; Yang, W.; et al. Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates nuclear factor-κB in hepatocellular carcinoma. J. Pathol. 2016, 238, 651–664. [Google Scholar] [CrossRef]
  31. Wan, M.; Huang, W.; Kute, T.E.; Miller, L.D.; Zhang, Q.; Hatcher, H.; Wang, J.; Stovall, D.B.; Russell, G.B.; Cao, P.D. Yin Yang 1 plays an essential role in breast cancer and negatively regulates p27. Am. J. Pathol. 2012, 180, 2120–2133. [Google Scholar] [CrossRef] [Green Version]
  32. de Nigris, F.; Zanella, L.; Cacciatore, F.; De Chiara, A.; Fazioli, F.; Chiappetta, G.; Apice, G.; Infante, T.; Monaco, M.; Rossiello, R.; et al. YY1 overexpression is associated with poor prognosis and metastasis-free survival in patients suffering osteosarcoma. BMC Cancer 2011, 11, 472. [Google Scholar] [CrossRef] [Green Version]
  33. Wang, H.; Garzon, R.; Sun, H.; Ladner, K.J.; Singh, R.; Dahlman, J.; Cheng, A.; Hall, B.M.; Qualman, S.J.; Chandler, D.S.; et al. NF-κB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell 2008, 14, 369–381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Xia, W.; Li, Y.; Wu, Z.; Wang, Y.; Xing, N.; Yang, W.; Wu, S. Transcription factor YY1 mediates epithelial-mesenchymal transition through the TGFβ signaling pathway in bladder cancer. Med. Oncol. 2020, 37, 93. [Google Scholar] [CrossRef] [PubMed]
  35. Qiao, K.; Ning, S.; Wan, L.; Wu, H.; Wang, Q.; Zhang, X.; Xu, S.; Pang, D. LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway. J. Exp. Clin. Cancer Res. 2019, 38, 418. [Google Scholar] [CrossRef] [Green Version]
  36. Wang, W.; Yue, Z.; Tian, Z.; Xie, Y.; Zhang, J.; She, Y.; Yang, B.; Ye, Y.; Yang, Y. Expression of Yin Yang 1 in cervical cancer and its correlation with E-cadherin expression and HPV16 E6. PLoS ONE 2018, 13, e0193340. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. He, G.; Wang, Q.; Zhou, Y.; Wu, X.; Wang, L.; Duru, N.; Kong, X.; Zhang, P.; Wan, B.; Sui, L.; et al. YY1 is a novel potential therapeutic target for the treatment of HPV infection-induced cervical cancer by arsenic trioxide. Int. J. Gynecol. Cancer 2011, 21, 1097–1104. [Google Scholar] [CrossRef] [Green Version]
  38. Chinnappan, D.; Xiao, D.; Ratnasari, A.; Andry, C.; King, T.C.; Weber, C.H. Transcription factor YY1 expression in human gastrointestinal cancer cells. Int. J. Oncol. 2009, 34, 1417–1423. [Google Scholar]
  39. Pothoulakis, C.; Torre-Rojas, M.; Duran-Padilla, M.A.; Gevorkian, J.; Zoras, O.; Chrysos, E.; Chalkiadakis, G.; Baritaki, S. CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis. Int. J. Cancer 2018, 142, 334–346. [Google Scholar] [CrossRef] [Green Version]
  40. Zhang, N.; Li, X.; Wu, C.W.; Dong, Y.; Cai, M.; Mok, M.T.S.; Wang, H.; Chen, J.; Ng, S.S.M.; Chen, M.; et al. microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene 2012, 32, 5078–5088. [Google Scholar] [CrossRef] [Green Version]
  41. Zhu, G.; Qian, M.; Lu, L.; Chen, Y.; Zhang, X.; Wu, Q.; Liu, Y.; Bian, Z.; Yang, Y.; Guo, S.; et al. O-GlcNAcylation of YY1 stimulates tumorigenesis in colorectal cancer cells by targeting SLC22A15 and AANAT. Carcinogenesis 2019, 40, 1121–1131. [Google Scholar] [CrossRef]
  42. Luo, J.; Jiang, X.; Cao, L.; Dai, K.; Zhang, S.; Ge, X.; Zhou, X.; Lu, X. Expression of YY1 correlates with progression and metastasis in esophageal squamous cell carcinomas. OncoTargets Ther. 2014, 7, 1753–1759. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Zheng, L.; Chen, Y.; Ye, L.; Jiao, W.; Song, H.; Mei, H.; Li, D.; Yang, F.; Li, H.; Huang, K.; et al. miRNA-584-3p inhibits gastric cancer progression by repressing Yin Yang 1- facilitated MMP-14 expression. Sci. Rep. 2017, 7, 8967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Kang, W.; Tong, J.H.M.; Chan, A.W.H.; Zhao, J.; Dong, Y.; Wang, S.; Yang, W.; Sin, F.M.C.; Ng, S.S.M.; Yu, J.; et al. Yin Yang 1 contributes to gastric carcinogenesis and its nuclear expression correlates with shorter survival in patients with early stage gastric adenocarcinoma. J. Transl. Med. 2014, 12, 80. [Google Scholar] [CrossRef] [Green Version]
  45. Baritaki, S.; Chatzinikola, A.M.; Vakis, A.F.; Soulitzis, N.; Karabetsos, D.A.; Neonakis, I.; Bonavida, B.; Spandidos, D.A. YY1 Over-Expression in Human Brain Gliomas and Meningiomas Correlates with TGF-β1, IGF-1 and FGF-2 mRNA Levels. Cancer Investig. 2009, 27, 184–192. [Google Scholar] [CrossRef]
  46. Waters, M.R.; Gupta, A.S.; Mockenhaupt, K.; Brown, L.N.; Biswas, D.D.; Kordula, T. RelB acts as a molecular switch driving chronic inflammation in glioblastoma multiforme. Oncogenesis 2019, 8, 37. [Google Scholar] [CrossRef] [Green Version]
  47. Li, J.; Song, J.; Guo, F. miR-186 reverses cisplatin resistance and inhibits the formation of the glioblastoma-initiating cell phenotype by degrading Yin Yang 1 in glioblastoma. Int. J. Mol. Med. 2018, 43, 517–524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Dukers, D.F.; van Galen, J.C.; Giroth, C.; Jansen, P.; Sewalt, R.G.A.B.; Otte, A.P.; Kluin-Nelemans, H.C.; Meijer, C.J.L.M.; Raaphorst, F.M. Unique polycomb gene expression pattern in Hodgkin’s lymphoma and Hodgkin’s lymphoma-derived cell lines. Am. J. Pathol. 2004, 164, 873–881. [Google Scholar] [CrossRef]
  49. Li, Z.-J.; Cheng, J.; Song, Y.; Li, H.-H.; Zheng, J.-F. LncRNA SNHG5 upregulation induced by YY1 contributes to angiogenesis via miR-26b/CTGF/VEGFA axis in acute myelogenous leukemia. Lab. Investig. 2021, 101, 341–352. [Google Scholar] [CrossRef]
  50. Antonio-Andres, G.; Martinez-Ruiz, G.U.; Morales-Martinez, M.; Jimenez-Hernandez, E.; Martinez-Torres, E.; Lopez-Perez, T.V.; Estrada-Abreo, L.A.; Patino-Lopez, G.; Juarez-Mendez, S.; Davila-Borja, V.M.; et al. Transcriptional Regulation of Yin-Yang 1 Expression through the Hypoxia Inducible Factor-1 in Pediatric Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2022, 23, 1728. [Google Scholar] [CrossRef]
  51. Antonio-Andrés, G.; Rangel-Santiago, J.; Tirado-Rodríguez, B.; Martinez-Ruiz, G.U.; Klunder-Klunder, M.; Vega, M.I.; Lopez-Martinez, B.; Jiménez-Hernández, E.; Torres Nava, J.; Medina-Sanson, A.; et al. Role of Yin Yang-1 (YY1) in the transcription regulation of the multi-drug resistance (MDR1) gene. Leuk. Lymphoma 2018, 59, 2628–2638. [Google Scholar] [CrossRef]
  52. Kim, J.S.; Son, S.H.; Kim, M.Y.; Choi, D.; Jang, I.-S.; Paik, S.S.; Chae, J.H.; Uversky, V.N.; Kim, C.G. Diagnostic and prognostic relevance of CP2c and YY1 expression in hepatocellular carcinoma. Oncotarget 2017, 8, 24389–24400. [Google Scholar] [CrossRef] [Green Version]
  53. Gao, D.; Wang, L.; Zhang, H.; Yan, X.; Yang, J.; Zhou, R.; Chang, X.; Sun, Y.; Tian, S.; Yao, Z.; et al. Spleen tyrosine kinase SYK(L) interacts with YY1 and coordinately suppresses SNAI2 transcription in lung cancer cells. FEBS J. 2018, 285, 4229–4245. [Google Scholar] [CrossRef] [Green Version]
  54. Zhao, G.; Li, Q.; Wang, A.; Jiao, J. YY1 regulates melanoma tumorigenesis through a miR-9 ~ RYBP axis. J. Exp. Clin. Cancer Res. 2015, 34, 66. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Palmer, M.B.; Majumder, P.; Cooper, J.C.; Yoon, H.; Wade, P.A.; Boss, J.M. Yin yang 1 regulates the expression of snail through a distal enhancer. Mol. Cancer Res. 2009, 7, 221–229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Du, J.; Ren, W.; Yao, F.; Wang, H.; Zhang, K.; Luo, M.; Shang, Y.; O’Connell, D.; Bei, Z.; Wang, H.; et al. YY1 cooperates with TFEB to regulate autophagy and lysosomal biogenesis in melanoma. Mol. Carcinog. 2019, 58, 2149–2160. [Google Scholar] [CrossRef]
  57. Huerta-Yepez, S.; Liu, H.; Baritaki, S.; Del Lourdes Cebrera-MuÑOz, M.; Rivera-Pazos, C.; Maldonado-Valenzuela, A.; Valencia-Hipolito, A.; Vega, M.I.; Chen, H.; Berenson, J.R.; et al. Overexpression of Yin Yang 1 in bone marrow-derived human multiple myeloma and its clinical significance. Int. J. Oncol. 2014, 45, 1184–1192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Li, M.; Liu, Y.; Wei, Y.; Wu, C.; Meng, H.; Niu, W.; Zhou, Y.; Wang, H.; Wen, Q.; Fan, S.; et al. Zinc-finger protein YY1 suppresses tumor growth of human nasopharyngeal carcinoma by inactivating c-Myc-mediated microRNA-141 transcription. J. Biol. Chem. 2019, 294, 6172–6187. [Google Scholar] [CrossRef] [Green Version]
  59. Hafsi, S.; Candido, S.; Maestro, R.; Falzone, L.; Soua, Z.; Bonavida, B.; Spandidos, D.A.; Libra, M. Correlation between the overexpression of Yin Yang 1 and the expression levels of miRNAs in Burkitt’s lymphoma: A computational study. Oncol. Lett. 2016, 11, 1021–1025. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Castellano, G.; Torrisi, E.; Ligresti, G.; Nicoletti, F.; Malaponte, G.; Traval, S.; McCubrey, J.A.; Canevari, S.; Libra, M. Yin Yang 1 overexpression in diffuse large B-cell lymphoma is associated with B-cell transformation and tumor progression. Cell Cycle 2010, 9, 557–563. [Google Scholar] [CrossRef] [Green Version]
  61. Vivarelli, S.; Falzone, L.; Ligresti, G.; Candido, S.; Garozzo, A.; Magro, G.G.; Bonavida, B.; Libra, M. Role of the transcription factor Yin Yang 1 and its selectively identified target Survivin in high-grade B-cells non-Hodgkin lymphomas: Potential diagnostic and therapeutic targets. Int. J. Mol. Sci. 2020, 21, 6446. [Google Scholar] [CrossRef] [PubMed]
  62. Sakhinia, E.; Glennie, C.; Hoyland, J.A.; Menasce, L.P.; Brady, G.; Miller, C.; Radford, J.A.; Byers, R.J. Clinical quantitation of diagnostic and predictive gene expression levels in follicular and diffuse large B-cell lymphoma by RT-PCR gene expression profiling. Blood 2007, 109, 3922–3928. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Naidoo, K.; Clay, V.; Hoyland, J.A.; Swindell, R.; Linton, K.; Illidge, T.; Radford, J.A.; Byers, R.J. YY1 expression predicts favourable outcome in follicular lymphoma. J. Clin. Pathol. 2010, 64, 125–129. [Google Scholar] [CrossRef]
  64. Qian, S.; Wang, W.; Li, M. Transcriptional factor Yin Yang 1 facilitates the stemness of ovarian cancer via suppressing miR-99a activity through enhancing its deacetylation level. Biomed. Pharmacother. 2020, 126, 110085. [Google Scholar] [CrossRef] [PubMed]
  65. Yang, H.; Zhang, X.; Zhu, L.; Yang, Y.; Yin, X. YY1-Induced lncRNA PART1 Enhanced Resistance of Ovarian Cancer Cells to Cisplatin by Regulating miR-512-3p/CHRAC1 Axis. DNA Cell Biol. 2021, 40, 821–832. [Google Scholar] [CrossRef]
  66. Jiang, W.; Zhao, S.; Shen, J.; Guo, L.; Sun, Y.; Zhu, Y.; Ma, Z.; Zhang, X.; Hu, Y.; Xiao, W.; et al. The MiR-135b-BMAL1-YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance. Cell Death Dis. 2018, 9, 149. [Google Scholar] [CrossRef] [Green Version]
  67. Huang, Y.; Tao, T.; Liu, C.; Guan, H.; Zhang, G.; Ling, Z.; Zhang, L.; Lu, K.; Chen, S.; Xu, B.; et al. Upregulation of miR-146a by YY1 depletion correlates with delayed progression of prostate cancer. Int. J. Oncol. 2017, 50, 421–431. [Google Scholar] [CrossRef] [Green Version]
  68. Zapata-Tarres, M.; Juarez-Villegas, L.E.; Maldonado-Valenzuela, A.; Baay-Guzman, G.J.; Lopez-Perez, T.V.; Cabrera-Muñoz, L.; Sadowinski-Pine, S.; Huerta-Yepez, S. Expression of YY1 in Wilms tumors with favorable histology is a risk factor for adverse outcomes. Future Oncol. 2019, 15, 1231–1241. [Google Scholar] [CrossRef]
  69. de Nigris, F.; Botti, C.; de Chiara, A.; Rossiello, R.; Apice, G.; Fazioli, F.; Fiorito, C.; Sica, V.; Napoli, C. Expression of transcription factor Yin Yang 1 in human osteosarcomas. Eur. J. Cancer 2006, 42, 2420–2424. [Google Scholar] [CrossRef]
  70. Gashaw, I.; Grümmer, R.; Klein-Hitpass, L.; Dushaj, O.; Bergmann, M.; Brehm, R.; Grobholz, R.; Kliesch, S.; Neuvians, T.P.; Schmid, K.W.; et al. Gene signatures of testicular seminoma with emphasis on expression of ets variant gene 4. Cell. Mol. Life Sci. 2005, 62, 2359–2368. [Google Scholar] [CrossRef]
  71. Zaravinos, A.; Spandidos, D.A. Yin yang 1 expression in human tumors. Cell Cycle 2010, 9, 512–522. [Google Scholar] [CrossRef] [Green Version]
  72. Arribas, J.; Castellví, J.; Marcos, R.; Zafón, C.; Velázquez, A. Expression of YY1 in Differentiated Thyroid Cancer. Endocr. Pathol. 2015, 26, 111–118. [Google Scholar] [CrossRef] [PubMed]
  73. Fang, M.; Huang, W.; Wu, X.; Gao, Y.; Ou, J.; Zhang, X.; Li, Y. MiR-141-3p Suppresses Tumor Growth and Metastasis in Papillary Thyroid Cancer via Targeting Yin Yang 1. Anat. Rec. 2019, 302, 258–268. [Google Scholar] [CrossRef] [PubMed]
  74. Wang, F.; Li, Z.; Sun, B. miR-544 inhibits the migration and invasion of anaplastic thyroid cancer by targeting Yin Yang-1. Oncol. Lett. 2019, 17, 2983–2992. [Google Scholar] [CrossRef] [PubMed]
  75. Liu, X.; Jutooru, I.; Lei, P.; Kim, K.; Lee, S.-o.; Brents, L.K.; Prather, P.L.; Safe, S. Betulinic Acid Targets YY1 and ErbB2 through Cannabinoid Receptor-Dependent Disruption of MicroRNA-27a: ZBTB10 in Breast CancerBetulinic Acid Downregulates ErbB2 in Breast Cancer Cells. Mol. Cancer Ther. 2012, 11, 1421–1431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Huerta-Yepez, S.; Baritaki, S.; Baay-Guzman, G.; Hernandez-Luna, M.A.; Hernandez-Cueto, A.; Vega, M.I.; Bonavida, B. Contribution of either YY1 or BclXL-induced inhibition by the NO-donor DETANONOate in the reversal of drug resistance, both in vitro and in vivo. YY1 and BclXL are overexpressed in prostate cancer. Nitric Oxide 2013, 29, 17–24. [Google Scholar] [CrossRef]
  77. Rafii, S.; Tashkandi, E.; Bukhari, N.; Al-Shamsi, H.O. Current status of CRISPR/Cas9 application in clinical cancer research: Opportunities and challenges. Cancers 2022, 14, 947. [Google Scholar] [CrossRef]
  78. Breier, D.; Peer, D. Genome editing in cancer: Challenges and potential opportunities. Bioact. Mater. 2023, 21, 394–402. [Google Scholar] [CrossRef]
  79. Xu, C.; Tsai, Y.-H.; Galbo Jr, P.M.; Gong, W.; Storey, A.J.; Xu, Y.; Byrum, S.D.; Xu, L.; Whang, Y.E.; Parker, J.S. Cistrome analysis of YY1 uncovers a regulatory axis of YY1: BRD2/4-PFKP during tumorigenesis of advanced prostate cancer. Nucleic Acids Res. 2021, 49, 4971–4988. [Google Scholar] [CrossRef]
  80. Sarvagalla, S.; Kolapalli, S.P.; Vallabhapurapu, S. The Two Sides of YY1 in Cancer: A Friend and a Foe. Front. Oncol. 2019, 9, 1230. [Google Scholar] [CrossRef] [Green Version]
  81. Hanahan, D. Hallmarks of cancer: New dimensions. Cancer Discov. 2022, 12, 31–46. [Google Scholar] [CrossRef]
  82. Hanahan, D.; Weinberg, R.A. The Hallmarks of Cancer. Cell 2000, 100, 57–70. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The Next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Wu, S.; Kasim, V.; Kano, M.R.; Tanaka, S.; Ohba, S.; Miura, Y.; Miyata, K.; Liu, X.; Matsuhashi, A.; Chung, U.-i.; et al. Transcription Factor YY1 Contributes to Tumor Growth by Stabilizing Hypoxia Factor HIF-1α in a p53-Independent Manner. Cancer Res. 2013, 73, 1787–1799. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Wu, S.; Wang, H.; Li, Y.; Xie, Y.; Huang, C.; Zhao, H.; Miyagishi, M.; Kasim, V. Transcription Factor YY1 Promotes Cell Proliferation by Directly Activating the Pentose Phosphate Pathway. Cancer Res. 2018, 78, 4549–4562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Santiago, F.; Ishii, H.; Shafi, S.; Khurana, R.; Kanellakis, P.; Bhindi, R.; Ramirez, M.; Bobik, A.; Martin, J.; Chesterman, C.; et al. Yin Yang-1 inhibits vascular smooth muscle cell growth and intimal thickening by repressing p21WAF1/Cip1 transcription and p21WAF1/Cip1-Cdk4-cyclin D1 assembly. Circ. Res. 2007, 101, 146–155. [Google Scholar] [CrossRef]
  87. Riggs, K.J.; Saleque, S.; Wong, K.K.; Merrell, K.T.; Lee, J.S.; Shi, Y.; Calame, K. Yin-yang 1 activates the c-myc promoter. Mol. Cell. Biol. 1993, 13, 7487–7495. [Google Scholar] [CrossRef] [PubMed]
  88. Sui, G.; El Bachir, A.; Shi, Y.; Brignone, C.; Wall, N.R.; Yin, P.; Donohoe, M.; Luke, M.P.; Calvo, D.; Grossman, S.R.; et al. Yin Yang 1 Is a Negative Regulator of p53. Cell 2004, 117, 859–872. [Google Scholar] [CrossRef] [Green Version]
  89. Grönroos, E.; Terentiev, A.A.; Punga, T.; Ericsson, J. YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc. Natl. Acad. Sci. USA 2004, 101, 12165–12170. [Google Scholar] [CrossRef] [PubMed]
  90. Sui, Y.; Wu, T.; Li, F.; Wang, F.; Cai, Y.; Jin, J. YY1/BCCIP Coordinately Regulates P53-Responsive Element (p53RE)-Mediated Transactivation of p21(Waf1/Cip1). Int. J. Mol. Sci. 2019, 20, 2095. [Google Scholar] [CrossRef] [Green Version]
  91. Wang, Y.; Wu, S.; Huang, C.; Li, Y.; Zhao, H.; Kasim, V. Yin Yang 1 promotes the Warburg effect and tumorigenesis via glucose transporter GLUT3. Cancer Sci. 2018, 109, 2423–2434. [Google Scholar] [CrossRef] [Green Version]
  92. Li, Y.; Kasim, V.; Yan, X.; Li, L.; Meliala, I.T.S.; Huang, C.; Li, Z.; Lei, K.; Song, G.; Zheng, X.; et al. Yin Yang 1 facilitates hepatocellular carcinoma cell lipid metabolism and tumor progression by inhibiting PGC-1β-induced fatty acid oxidation. Theranostics 2019, 9, 7599–7615. [Google Scholar] [CrossRef]
  93. Li, Y.; Li, J.; Li, Z.; Wei, M.; Zhao, H.; Miyagishi, M.; Wu, S.; Kasim, V. Homeostasis Imbalance of YY2 and YY1 Promotes Tumor Growth by Manipulating Ferroptosis. Adv. Sci. 2022, 9, e2104836. [Google Scholar] [CrossRef]
  94. Peng, Y.; Wang, Y.; Zhou, C.; Mei, W.; Zeng, C. PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? Front. Oncol. 2022, 12, 819128. [Google Scholar] [CrossRef]
  95. Yang, Y.; Zhou, L.; Lu, L.; Wang, L.; Li, X.; Jiang, P.; Chan, L.K.Y.; Zhang, T.; Yu, J.; Kwong, J.; et al. A novel miR-193a-5p-YY1-APC regulatory axis in human endometrioid endometrial adenocarcinoma. Oncogene 2012, 32, 3432–3442. [Google Scholar] [CrossRef]
  96. Potluri, V.; Noothi, S.K.; Vallabhapurapu, S.D.; Yoon, S.-O.; Driscoll, J.J.; Lawrie, C.H.; Vallabhapurapu, S. Transcriptional repression of Bim by a novel YY1-RelA complex is essential for the survival and growth of Multiple Myeloma. PLoS ONE 2013, 8, e66121. [Google Scholar] [CrossRef] [Green Version]
  97. Wang, X.; Feng, Y.; Xu, L.; Chen, Y.; Zhang, Y.; Su, D.; Ren, G.; Lu, J.; Huang, B. YY1 restrained cell senescence through repressing the transcription of p16. Biochim. Biophys. Acta 2008, 1783, 1876–1883. [Google Scholar] [CrossRef] [Green Version]
  98. Shalapour, S.; Karin, M. Immunity, inflammation, and cancer: An eternal fight between good and evil. J. Clin. Investig. 2015, 125, 3347–3355. [Google Scholar] [CrossRef] [Green Version]
  99. Liu, D.; Zhang, J.; Wu, Y.; Shi, G.; Yuan, H.; Lu, Z.; Zhu, Q.; Wu, P.; Lu, C.; Guo, F.; et al. YY1 suppresses proliferation and migration of pancreatic ductal adenocarcinoma by regulating the CDKN3/MdM2/P53/P21 signaling pathway. Int. J. Cancer. 2017, 142, 1392–1404. [Google Scholar] [CrossRef] [Green Version]
  100. Miller, D.M.; Thomas, S.D.; Islam, A.; Muench, D.; Sedoris, K. c-Myc and cancer metabolism. Clin. Cancer Res. 2012, 18, 5546–5553. [Google Scholar] [CrossRef] [Green Version]
  101. Joo, M.; Wright, J.G.; Hu, N.N.; Sadikot, R.T.; Park, G.Y.; Blackwell, T.S.; Christman, J.W. Yin Yang 1 enhances cyclooxygenase-2 gene expression in macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 2007, 292, L1219–L1226. [Google Scholar] [CrossRef] [Green Version]
  102. Pu, D.; Yin, L.; Huang, L.; Qin, C.; Zhou, Y.; Wu, Q.; Li, Y.; Zhou, Q.; Li, L. Cyclooxygenase-2 Inhibitor: A Potential Combination Strategy With Immunotherapy in Cancer. Front. Oncol. 2021, 11, 637504. [Google Scholar] [CrossRef]
  103. de Nigris, F.; Crudele, V.; Giovane, A.; Casamassimi, A.; Giordano, A.; Garban, H.J.; Cacciatore, F.; Pentimalli, F.; Marquez-Garban, D.C.; Petrillo, A.; et al. CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy. Proc. Natl. Acad. Sci. USA 2010, 107, 14484–14489. [Google Scholar] [CrossRef]
  104. Chen, Y.; Jacamo, R.; Konopleva, M.; Garzon, R.; Croce, C.; Andreeff, M. CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. J. Clin. Investig. 2013, 123, 2395–2407. [Google Scholar] [CrossRef] [Green Version]
  105. Zhang, Y.; Liu, J.; Wang, S.; Luo, X.; Li, Y.; Lv, Z.; Zhu, J.; Lin, J.; Ding, L.; Ye, Q. The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners. Oncotarget 2016, 7, 23740–23756. [Google Scholar] [CrossRef]
  106. Sitwala, K.V.; Adams, K.; Markovitz, D.M. YY1 and NF-Y binding sites regulate the transcriptional activity of the dek and dek-can promoter. Oncogene 2002, 21, 8862–8870. [Google Scholar] [CrossRef] [Green Version]
  107. Baritaki, S.; Huerta-Yepez, S.; Sakai, T.; Spandidos, D.A.; Bonavida, B. Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: Up-regulation of DR5 and inhibition of Yin Yang 1. Mol. Cancer Ther. 2007, 6, 1387–1399. [Google Scholar] [CrossRef] [Green Version]
  108. Bonavida, B. Rituximab-induced inhibition of antiapoptotic cell survival pathways: Implications in chemo/immunoresistance, rituximab unresponsiveness, prognostic and novel therapeutic interventions. Oncogene 2007, 26, 3629–3636. [Google Scholar] [CrossRef] [Green Version]
  109. Huang, H.-C.; Chao, C.-C.; Wu, P.-H.; Chung, H.-Y.; Lee, H.-Y.; Suen, C.-S.; Hwang, M.-J.; Cai, B.-H.; Kannagi, R. Epigenetic silencing of the synthesis of immunosuppressive Siglec ligand glycans by NF-κB/EZH2/YY1 axis in early-stage colon cancers. Biochim. Biophys. Acta 2019, 1862, 173–183. [Google Scholar] [CrossRef]
  110. Yao, R.; Jiang, H.; Ma, Y.; Wang, L.; Wang, L.; Du, J.; Hou, P.; Gao, Y.; Zhao, L.; Wang, G.; et al. PRMT7 Induces Epithelial-to-Mesenchymal Transition and Promotes Metastasis in Breast Cancer. Cancer Res. 2014, 74, 5656–5667. [Google Scholar] [CrossRef] [Green Version]
  111. Yin, D.; Ogawa, S.; Kawamata, N.; Leiter, A.; Ham, M.; Li, D.; Doan, N.B.; Said, J.W.; Black, K.L.; Phillip Koeffler, H. miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme. Oncogene 2013, 32, 1155–1163. [Google Scholar] [CrossRef] [Green Version]
  112. Tseng, H.Y.; Chen, Y.A.; Jen, J.; Shen, P.C.; Chen, L.M.; Lin, T.D.; Wang, Y.C.; Hsu, H.L. Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression. Oncogenesis 2017, 6, e313. [Google Scholar] [CrossRef] [Green Version]
  113. Allouche, A.; Nolens, G.; Tancredi, A.; Delacroix, L.; Mardaga, J.; Fridman, V.; Winkler, R.; Boniver, J.; Delvenne, P.; Begon, D.Y. The combined immunodetection of AP-2alpha and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors. Breast Cancer Res. 2008, 10, R9. [Google Scholar] [CrossRef]
  114. Macheda, M.L.; Rogers, S.; Best, J.D. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell. Physiol. 2004, 202, 654–662. [Google Scholar] [CrossRef]
  115. Hyuga, S.; Wada, H.; Eguchi, H.; Otsuru, T.; Iwgami, Y.; Yamada, D.; Noda, T.; Asaoka, T.; Kawamoto, K.; Gotoh, K.; et al. Expression of carbonic anhydrase IX is associated with poor prognosis through regulation of the epithelial-mesenchymal transition in hepatocellular carcinoma. Int. J. Oncol. 2017, 51, 1179–1190. [Google Scholar] [CrossRef] [Green Version]
  116. Chafe, S.C.; McDonald, P.C.; Saberi, S.; Nemirovsky, O.; Venkateswaran, G.; Burugu, S.; Gao, D.; Delaidelli, A.; Kyle, A.H.; Baker, J.H.E.; et al. Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically. Cancer Immunol. Res. 2019, 7, 1064–1078. [Google Scholar] [CrossRef] [Green Version]
  117. Fu, Q.; Yu, Z. Phosphoglycerate kinase 1 (PGK1) in cancer: A promising target for diagnosis and therapy. Life Sci. 2020, 256, 117863. [Google Scholar] [CrossRef]
  118. Yang, T.; An, Z.; Zhang, C.; Wang, Z.; Wang, X.; Liu, Y.; Du, E.; Liu, R.; Zhang, Z.; Xu, Y. HnRNPM is a potential mediator of YY1 which promotes EMT in prostate cancer cells. Prostate 2019, 79, 1199–1210. [Google Scholar] [CrossRef]
  119. Pentland, I.; Campos-León, K.; Cotic, M.; Davies, K.-J.; Wood, C.D.; Groves, I.J.; Burley, M.; Coleman, N.; Stockton, J.D.; Noyvert, B.; et al. Disruption of CTCF-YY1-dependent looping of the human papillomavirus genome activates differentiation-induced viral oncogene transcription. PLoS Biol. 2018, 16, e2005752. [Google Scholar] [CrossRef] [Green Version]
  120. Morales-Martinez, M.; Valencia-Hipolito, A.; Vega, G.G.; Neri, N.; Nambo, M.J.; Alvarado, I.; Cuadra, I.; Duran-Padilla, M.A.; Martinez-Maza, O.; Huerta-Yepez, S.; et al. Regulation of Krüppel-Like Factor 4 (KLF4) expression through the transcription factor Yin-Yang 1 (YY1) in non-Hodgkin B-cell lymphoma. Oncotarget 2019, 10, 2173–2188. [Google Scholar] [CrossRef] [Green Version]
  121. Zhao, J.-L.; Huang, F.; He, F.; Gao, C.-C.; Liang, S.-Q.; Ma, P.-F.; Dong, G.-Y.; Han, H.; Qin, H.-Y. Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages. Cancer Res. 2016, 76, 1403–1415. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Fu, S.H.; Lai, M.C.; Zheng, Y.Y.; Sun, Y.W.; Qiu, J.J.; Gui, F.; Zhang, Q.; Liu, F. MiR-195 inhibits the ubiquitination and degradation of YY1 by Smurf2, and induces EMT and cell permeability of retinal pigment epithelial cells. Cell Death Dis. 2021, 12, 708. [Google Scholar] [CrossRef] [PubMed]
  123. Yang, C.; Zhang, J.-J.; Peng, Y.-P.; Zhu, Y.; Yin, L.-D.; Wei, J.-S.; Gao, W.-T.; Jiang, K.-R.; Miao, Y. A Yin-Yang 1/miR-30a regulatory circuit modulates autophagy in pancreatic cancer cells. J. Transl. Med. 2017, 15, 211. [Google Scholar] [CrossRef] [Green Version]
  124. Feng, L.; Ma, Y.; Sun, J.; Shen, Q.; Liu, L.; Lu, H.; Wang, F.; Yue, Y.; Li, J.; Zhang, S.; et al. YY1-MIR372-SQSTM1 regulatory axis in autophagy. Autophagy 2014, 10, 1442–1453. [Google Scholar] [CrossRef] [Green Version]
  125. Bensaad, K.; Tsuruta, A.; Selak, M.A.; Vidal, M.N.C.; Nakano, K.; Bartrons, R.; Gottlieb, E.; Vousden, K.H. TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis. Cell 2006, 126, 107–120. [Google Scholar] [CrossRef] [Green Version]
  126. Ramkumar, C.; Cui, H.; Kong, Y.; Jones, S.N.; Gerstein, R.M.; Zhang, H. Smurf2 suppresses B-cell proliferation and lymphomagenesis by mediating ubiquitination and degradation of YY1. Nat. Commun. 2013, 4, 2598. [Google Scholar] [CrossRef] [Green Version]
  127. Jeong, H.M.; Lee, S.H.; Yum, J.; Yeo, C.Y.; Lee, K.Y. Smurf2 regulates the degradation of YY1. Biochim. Biophys. Acta 2014, 1843, 2005–2011. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Wu, S.; Murai, S.; Kataoka, K.; Miyagishi, M. Yin Yang 1 induces transcriptional activity of p73 through cooperation with E2F1. Biochem. Biophys. Res. Commun. 2008, 365, 75–81. [Google Scholar] [CrossRef]
  129. Zhan, S.; Wang, T.; Ge, W.; Li, J. Multiple roles of Ring 1 and YY1 binding protein in physiology and disease. J. Cell. Mol. Med. 2018, 22, 2046–2054. [Google Scholar] [CrossRef]
  130. Bajusz, I.; Henry, S.; Sutus, E.; Kovács, G.; Pirity, M.K. Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription. Genes 2019, 10, 941. [Google Scholar] [CrossRef] [Green Version]
  131. Chen, Q.; Yang, C.; Chen, L.; Zhang, J.-J.; Ge, W.-L.; Yuan, H.; Meng, L.-D.; Huang, X.-M.; Shen, P.; Miao, Y.; et al. YY1 targets tubulin polymerisation-promoting protein to inhibit migration, invasion and angiogenesis in pancreatic cancer via p38/MAPK and PI3K/AKT pathways. Br. J. Cancer 2019, 121, 912–921. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Yang, W.; Li, Z.; Qin, R.; Wang, X.; An, H.; Wang, Y.; Zhu, Y.; Liu, Y.; Cai, S.; Chen, S.; et al. YY1 Promotes Endothelial Cell-Dependent Tumor Angiogenesis in Hepatocellular Carcinoma by Transcriptionally Activating VEGFA. Front. Oncol. 2019, 9, 1187. [Google Scholar] [CrossRef] [PubMed]
  133. Kojima, T.; Nakahama, K.-I.; Yamamoto, K.; Uematsu, H.; Morita, I. Age-and cell cycle-dependent changes in EPC-1/PEDF promoter activity in human diploid fibroblast-like (HDF) cells. Mol. Cell. Biochem. 2006, 293, 63–69. [Google Scholar] [CrossRef]
  134. Zhang, J.-J.; Zhu, Y.; Xie, K.-L.; Peng, Y.-P.; Tao, J.-Q.; Tang, J.; Li, Z.; Xu, Z.-K.; Dai, C.-C.; Qian, Z.-Y.; et al. Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism. Mol. Cancer 2014, 13, 130. [Google Scholar] [CrossRef] [Green Version]
  135. Wang, W.; Li, D.; Sui, G. YY1 Is an Inducer of Cancer Metastasis. Crit. Rev. Oncog. 2017, 22, 1–11. [Google Scholar] [CrossRef] [PubMed]
  136. Mani, S.A.; Guo, W.; Liao, M.-J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133, 704–715. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Bracken, C.P.; Goodall, G.J. The many regulators of epithelial− mesenchymal transition. Nat. Rev. Mol. Cell Biol. 2022, 23, 89–90. [Google Scholar] [CrossRef]
  138. Han, J.; Meng, J.; Chen, S.; Wang, X.; Yin, S.; Zhang, Q.; Liu, H.; Qin, R.; Li, Z.; Zhong, W.; et al. YY1 Complex Promotes Quaking Expression via Super-Enhancer Binding during EMT of Hepatocellular Carcinoma. Cancer Res. 2019, 79, 1451–1464. [Google Scholar] [CrossRef] [Green Version]
  139. Hwang, S.S.; Kim, Y.U.; Lee, S.; Jang, S.W.; Kim, M.K.; Koh, B.H.; Lee, W.; Kim, J.; Souabni, A.; Busslinger, M. Transcription factor YY1 is essential for regulation of the Th2 cytokine locus and for Th2 cell differentiation. Proc. Natl. Acad. Sci. USA 2013, 110, 276–281. [Google Scholar] [CrossRef]
  140. Hwang, S.S.; Jang, S.W.; Kim, M.K.; Kim, L.K.; Kim, B.-S.; Kim, H.S.; Kim, K.; Lee, W.; Flavell, R.A.; Lee, G.R. YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity. Nat. Commun. 2016, 7, 10789. [Google Scholar] [CrossRef] [Green Version]
  141. Banerjee, A.; Sindhava, V.; Vuyyuru, R.; Jha, V.; Hodewadekar, S.; Manser, T.; Atchison, M.L. YY1 is required for germinal center B cell development. PLoS ONE 2016, 11, e0155311. [Google Scholar] [CrossRef] [Green Version]
  142. Elinav, E.; Nowarski, R.; Thaiss, C.A.; Hu, B.; Jin, C.; Flavell, R.A. Inflammation-induced cancer: Crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 2013, 13, 759–771. [Google Scholar] [CrossRef]
  143. Vasan, N.; Baselga, J.; Hyman, D.M. A view on drug resistance in cancer. Nature 2019, 575, 299–309. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Ward, R.A.; Fawell, S.; Floc’h, N.; Flemington, V.; McKerrecher, D.; Smith, P.D. Challenges and opportunities in cancer drug resistance. Chem. Rev. 2020, 121, 3297–3351. [Google Scholar] [CrossRef] [PubMed]
  145. Garbán, H.J.; Bonavida, B. Nitric Oxide Inhibits the Transcription Repressor Yin-Yang 1 Binding Activity at the Silencer Region of the Fas Promoter: A Pivotal Role for Nitric Oxide in the Up-Regulation of Fas Gene Expression in Human Tumor Cells. J. Immunol. 2001, 167, 75–81. [Google Scholar] [CrossRef] [Green Version]
  146. Van Nguyen, T.; Puebla-Osorio, N.; Pang, H.; Dujka, M.E.; Zhu, C. DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: A mouse model. J. Exp. Med. 2007, 204, 1453–1461. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Lee, M.; Lahusen, T.; Wang, R.; Xiao, C.; Xu, X.; Hwang, Y.; He, W.; Shi, Y.; Deng, C. Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene 2012, 31, 116–127. [Google Scholar] [CrossRef] [PubMed]
  148. Hays, E.; Bonavida, B. Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies. Antioxidants 2019, 8, 407. [Google Scholar] [CrossRef] [Green Version]
  149. Bonavida, B. Sensitizing activities of nitric oxide donors for cancer resistance to anticancer therapeutic drugs. Biochem. Pharmacol. 2020, 176, 113913. [Google Scholar] [CrossRef]
  150. Huerta-Yepez, S.; Vega, M.; Jazirehi, A.; Garban, H.; Hongo, F.; Cheng, G.; Bonavida, B. Nitric oxide sensitizes prostate carcinoma cell lines to TRAIL-mediated apoptosis via inactivation of NF-κB and inhibition of Bcl-xL expression. Oncogene 2004, 23, 4993–5003. [Google Scholar] [CrossRef] [Green Version]
  151. Stewart, G.D.; Nanda, J.; Katz, E.; Bowman, K.J.; Christie, J.G.; Brown, D.G.; McLaren, D.B.; Riddick, A.C.; Ross, J.A.; Jones, G.D. DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions. Biochem. Pharmacol. 2011, 81, 203–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Bonavida, B.; Garban, H. Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics. Redox Biol. 2015, 6, 486–494. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Bjerkvig, R.; Tysnes, B.B.; Aboody, K.S.; Najbauer, J.; Terzis, A. The origin of the cancer stem cell: Current controversies and new insights. Nat. Rev. Cancer 2005, 5, 899–904. [Google Scholar] [CrossRef] [PubMed]
  154. Lobo, N.A.; Shimono, Y.; Qian, D.; Clarke, M.F. The Biology of Cancer Stem Cells. Annu. Rev. Cell Dev. Biol. 2007, 23, 675–699. [Google Scholar] [CrossRef] [Green Version]
  155. Yang, L.; Shi, P.; Zhao, G.; Xu, J.; Peng, W.; Zhang, J.; Zhang, G.; Wang, X.; Dong, Z.; Chen, F. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct. Target Ther. 2020, 5, 8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Kaufhold, S.; Garbán, H.; Bonavida, B. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J. Exp. Clin. Cancer Res. 2016, 35, 84. [Google Scholar] [CrossRef] [Green Version]
  157. Guo, Q.; Wang, T.; Yang, Y.; Gao, L.; Zhao, Q.; Zhang, W.; Xi, T.; Zheng, L. Transcriptional factor Yin Yang 1 promotes the stemness of breast cancer cells by suppressing miR-873-5p transcriptional activity. Mol. Ther. Nucleic Acids 2020, 21, 527–541. [Google Scholar] [CrossRef]
  158. You, J.; Tao, B.; Peng, L.; Peng, T.; He, H.; Zeng, S.; Han, J.; Chen, L.; Xia, X.; Yang, X. Transcription factor YY1 mediates self-renewal of glioblastoma stem cells through regulation of the SENP1/METTL3/MYC axis. Cancer Gene Ther. 2022, 30, 683–693. [Google Scholar] [CrossRef]
  159. Bonavida, B. Overexpression of YY1 Regulates the Resistance of Cancer Stem Cells: Targeting YY1. In Cancer Stem Cell Resistance to Targeted Therapy; Springer: Cham, Switzerland, 2019; pp. 93–113. [Google Scholar]
  160. Li, H.; Li, T.; Huang, D.; Zhang, P. Long noncoding RNA SNHG17 induced by YY1 facilitates the glioma progression through targeting miR-506-3p/CTNNB1 axis to activate Wnt/β-catenin signaling pathway. Cancer Cell Int. 2020, 20, 29. [Google Scholar] [CrossRef] [Green Version]
  161. Zhong, L.; Li, Y.; Xiong, L.; Wang, W.; Wu, M.; Yuan, T.; Yang, W.; Tian, C.; Miao, Z.; Wang, T. Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives. Signal Transduct. Target Ther. 2021, 6, 201. [Google Scholar] [CrossRef]
  162. Bedard, P.L.; Hyman, D.M.; Davids, M.S.; Siu, L.L. Small molecules, big impact: 20 years of targeted therapy in oncology. Lancet 2020, 395, 1078–1088. [Google Scholar] [CrossRef] [PubMed]
  163. Bonavida, B. Therapeutic YY1 Inhibitors in Cancer: ALL in ONE. Crit. Rev. Oncog. 2017, 22, 37–47. [Google Scholar] [CrossRef] [PubMed]
  164. Hongo, F.; Garban, H.; Huerta-Yepez, S.; Vega, M.; Jazirehi, A.R.; Mizutani, Y.; Miki, T.; Bonavida, B. Inhibition of the transcription factor Yin Yang 1 activity by S-nitrosation. Biochem. Biophys. Res. Commun. 2005, 336, 692–701. [Google Scholar] [CrossRef]
  165. Sato, Y.; Yoshino, H.; Tsuruga, E.; Kashiwakura, I. Fas ligand enhances apoptosis of human lung cancer cells cotreated with RIG-I-like receptor agonist and radiation. Curr. Cancer Drug Targets 2020, 20, 372–381. [Google Scholar] [CrossRef] [PubMed]
  166. Carneiro, B.A.; El-Deiry, W.S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 2020, 17, 395–417. [Google Scholar] [CrossRef]
  167. Yasuda, H. Solid tumor physiology and hypoxia-induced chemo/radio-resistance: Novel strategy for cancer therapy: Nitric oxide donor as a therapeutic enhancer. Nitric Oxide 2008, 19, 205–216. [Google Scholar] [CrossRef]
  168. Ribeiro, E.; Costa, B.; Vasques-Nóvoa, F.; Vale, N. In Vitro Drug Repurposing: Focus on Vasodilators. Cells 2023, 12, 671. [Google Scholar] [CrossRef]
  169. Reynaert, N.L.; Ckless, K.; Korn, S.H.; Vos, N.; Guala, A.S.; Wouters, E.F.; van der Vliet, A.; Janssen-Heininger, Y.M. Nitric oxide represses inhibitory κB kinase through S-nitrosylation. Proc. Natl. Acad. Sci. USA 2004, 101, 8945–8950. [Google Scholar] [CrossRef]
  170. Kelleher, Z.T.; Matsumoto, A.; Stamler, J.S.; Marshall, H.E. NOS2 regulation of NF-κB by S-nitrosylation of p65. J. Biol. Chem. 2007, 282, 30667–30672. [Google Scholar] [CrossRef] [Green Version]
  171. Scicinski, J.; Oronsky, B.; Ning, S.; Knox, S.; Peehl, D.; Kim, M.M.; Langecker, P.; Fanger, G. NO to cancer: The complex and multifaceted role of nitric oxide and the epigenetic nitric oxide donor, RRx-001. Redox Biol. 2015, 6, 1–8. [Google Scholar] [CrossRef] [Green Version]
  172. Oronsky, B.; Scicinski, J.; Ning, S.; Peehl, D.; Oronsky, A.; Cabrales, P.; Bednarski, M.; Knox, S. RRx-001, A novel dinitroazetidine radiosensitizer. Investig. New Drugs 2016, 34, 371–377. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Oronsky, B.; Caroen, S.; Abrouk, N.; Reid, T.R. RRx-001 and the “Right stuff”: Protection and treatment in outer space. Life Sci. Space Res. 2022, 35, 69–75. [Google Scholar] [CrossRef] [PubMed]
  174. Alakurtti, S.; Mäkelä, T.; Koskimies, S.; Yli-Kauhaluoma, J. Pharmacological properties of the ubiquitous natural product betulin. Eur. J. Pharm. Sci. 2006, 29, 1–13. [Google Scholar] [CrossRef]
  175. Fulda, S. Betulinic Acid for cancer treatment and prevention. Int. J. Mol. Sci. 2008, 9, 1096–1107. [Google Scholar] [CrossRef] [Green Version]
  176. Pisha, E.; Chai, H.; Lee, I.-S.; Chagwedera, T.E.; Farnsworth, N.R.; Cordell, G.A.; Beecher, C.W.W.; Fong, H.H.S.; Kinghorn, A.D.; Brown, D.M.; et al. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat. Med. 1995, 1, 1046–1051. [Google Scholar] [CrossRef]
  177. Fulda, S.; Kroemer, G. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov. Today 2009, 14, 885–890. [Google Scholar] [CrossRef] [PubMed]
  178. Fulda, S.; Scaffidi, C.; Susin, S.A.; Krammer, P.H.; Kroemer, G.; Peter, M.E.; Debatin, K.-M. Activation of Mitochondria and Release of Mitochondrial Apoptogenic Factors by Betulinic Acid. J. Biol. Chem. 1998, 273, 33942–33948. [Google Scholar] [CrossRef] [Green Version]
  179. Chintharlapalli, S.; Papineni, S.; Lei, P.; Pathi, S.; Safe, S. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer 2011, 11, 371. [Google Scholar] [CrossRef] [Green Version]
  180. Begon, D.Y.; Delacroix, L.; Vernimmen, D.; Jackers, P.; Winkler, R. Yin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells. J. Biol. Chem. 2005, 280, 24428–24434. [Google Scholar] [CrossRef] [Green Version]
  181. Mertens-Talcott, S.U.; Noratto, G.D.; Li, X.; Angel-Morales, G.; Bertoldi, M.C.; Safe, S. Betulinic acid decreases ER-negative breast cancer cell growth in vitro and in vivo: Role of Sp transcription factors and microRNA-27a: ZBTB10. Mol. Carcinog. 2013, 52, 591–602. [Google Scholar] [CrossRef] [Green Version]
  182. Sawada, N.; Kataoka, K.; Kondo, K.; Arimochi, H.; Fujino, H.; Takahashi, Y.; Miyoshi, T.; Kuwahara, T.; Monden, Y.; Ohnishi, Y. Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. Br. J. Cancer 2004, 90, 1672–1678. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Jiang, W.; Li, X.; Dong, S.; Zhou, W. Betulinic acid in the treatment of tumour diseases: Application and research progress. Biomed. Pharmacother. 2021, 142, 111990. [Google Scholar] [CrossRef] [PubMed]
  184. Zhai, Z.; Ren, Y.; Shu, C.; Chen, D.; Liu, X.; Liang, Y.; Li, A.; Zhou, J. JAC1 targets YY1 mediated JWA/p38 MAPK signaling to inhibit proliferation and induce apoptosis in TNBC. Cell Death Discov. 2022, 8, 169. [Google Scholar] [CrossRef]
  185. Ren, Y.; Chen, D.; Zhai, Z.; Chen, J.; Li, A.; Liang, Y.; Zhou, J. JAC1 suppresses proliferation of breast cancer through the JWA/p38/SMURF1/HER2 signaling. Cell Death Discov. 2021, 7, 85. [Google Scholar] [CrossRef]
  186. Qian, J.; Zhu, W.; Wang, K.; Ma, L.; Xu, J.; Xu, T.; Røe, O.D.; Li, A.; Zhou, J.; Shu, Y. JWA loss promotes cell migration and cytoskeletal rearrangement by affecting HER2 expression and identifies a high-risk subgroup of HER2-positive gastric carcinoma patients. Oncotarget 2016, 7, 36865. [Google Scholar] [CrossRef]
  187. Wang, S.; Gong, Z.; Chen, R.; Liu, Y.; Li, A.; Li, G.; Zhou, J. JWA regulates XRCC1 and functions as a novel base excision repair protein in oxidative-stress-induced DNA single-strand breaks. Nucleic Acids Res. 2009, 37, 1936–1950. [Google Scholar] [CrossRef] [Green Version]
  188. Ding, K.; Liu, X.; Wang, L.; Zou, L.; Jiang, X.; Li, A.; Zhou, J. Targeting JWA for Cancer Therapy: Functions, Mechanisms and Drug Discovery. Cancers 2022, 14, 4655. [Google Scholar] [CrossRef] [PubMed]
  189. Setrerrahmane, S.; Li, M.; Zoghbi, A.; Lv, X.; Zhang, S.; Zhao, W.; Lu, J.; Craik, D.J.; Xu, H. Cancer-related micropeptides encoded by ncRNAs: Promising drug targets and prognostic biomarkers. Cancer Lett. 2022, 547, 215723. [Google Scholar] [CrossRef]
  190. Xing, J.; Liu, H.; Jiang, W.; Wang, L. LncRNA-encoded peptide: Functions and predicting methods. Front. Oncol. 2021, 10, 622294. [Google Scholar] [CrossRef]
  191. Pueyo, J.I.; Magny, E.G.; Couso, J.P. New peptides under the s (ORF) ace of the genome. Trends Biochem. Sci. 2016, 41, 665–678. [Google Scholar] [CrossRef]
  192. Pauli, A.; Valen, E.; Schier, A.F. Identifying (non-) coding RNAs and small peptides: Challenges and opportunities. Bioessays 2015, 37, 103–112. [Google Scholar] [CrossRef] [Green Version]
  193. Chen, Y.; Ho, L.; Tergaonkar, V. sORF-Encoded MicroPeptides: New players in inflammation, metabolism, and precision medicine. Cancer Lett. 2021, 500, 263–270. [Google Scholar] [CrossRef] [PubMed]
  194. Wu, S.; Zhang, L.; Deng, J.; Guo, B.; Li, F.; Wang, Y.; Wu, R.; Zhang, S.; Lu, J.; Zhou, Y. A Novel Micropeptide Encoded by Y-Linked LINC00278 Links Cigarette Smoking and AR Signaling in Male Esophageal Squamous Cell CarcinomaRole of Micropeptide Encoded by lncRNA in Male ESCC. Cancer Res. 2020, 80, 2790–2803. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  195. Qiao, S.; Wang, W.; Yi, C.; Xu, Q.; Wang, W.; Shi, J.; Stovall, D.B.; Li, D.; Sui, G. YY1 Oligomerization Is Regulated by Its OPB Domain and Competes with Its Regulation of Oncoproteins. Cancers 2022, 14, 1611. [Google Scholar] [CrossRef] [PubMed]
  196. Zhang, Q.; Wan, M.; Shi, J.; Horita, D.A.; Miller, L.D.; Kute, T.E.; Kridel, S.J.; Kulik, G.; Sui, G. Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation. J. Mol. Cell Biol. 2016, 8, 232–243. [Google Scholar] [CrossRef] [Green Version]
  197. Yi, C.; Li, G.; Wang, W.; Sun, Y.; Zhang, Y.; Zhong, C.; Stovall, D.B.; Li, D.; Shi, J.; Sui, G. Disruption of YY1-EZH2 interaction using synthetic peptides inhibits breast cancer development. Cancers 2021, 13, 2402. [Google Scholar] [CrossRef]
  198. Qi, Y.; Yan, T.; Chen, L.; Zhang, Q.; Wang, W.; Han, X.; Li, D.; Shi, J.; Sui, G. Characterization of YY1 OPB peptide for its anticancer activity. Curr. Cancer Drug Targets 2019, 19, 504–511. [Google Scholar] [CrossRef]
  199. Wang, H.; Hertlein, E.; Bakkar, N.; Sun, H.; Acharyya, S.; Wang, J.; Carathers, M.; Davuluri, R.; Guttridge, D.C. NF-κB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes. Mol. Cell. Biol. 2007, 27, 4374–4387. [Google Scholar] [CrossRef] [Green Version]
  200. Zinatizadeh, M.R.; Schock, B.; Chalbatani, G.M.; Zarandi, P.K.; Jalali, S.A.; Miri, S.R. The Nuclear Factor Kappa B (NF-κB) signaling in cancer development and immune diseases. Genes Dis. 2021, 8, 287–297. [Google Scholar] [CrossRef]
  201. Focosi, D.; Tuccori, M.; Maggi, F. Progressive multifocal leukoencephalopathy and anti-CD20 monoclonal antibodies: What do we know after 20 years of rituximab. Rev. Med. Virol. 2019, 29, e2077. [Google Scholar] [CrossRef]
  202. Byrd, J.C.; Kitada, S.; Flinn, I.W.; Aron, J.L.; Pearson, M.; Lucas, D.; Reed, J.C. The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: Evidence of caspase activation and apoptosis induction. Blood 2002, 99, 1038–1043. [Google Scholar] [CrossRef]
  203. Jazirehi, A.R.; Huerta-Yepez, S.; Cheng, G.; Bonavida, B. Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-κB signaling pathway in non-Hodgkin’s lymphoma B-cell lines: Role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Res. 2005, 65, 264–276. [Google Scholar] [CrossRef] [PubMed]
  204. Vega, M.I.; Jazirehi, A.R.; Huerta-Yepez, S.; Bonavida, B. Rituximab-induced inhibition of YY1 and Bcl-xL expression in Ramos non-Hodgkin’s lymphoma cell line via inhibition of NF-κB activity: Role of YY1 and Bcl-xL in Fas resistance and chemoresistance, respectively. J. Immunol. 2005, 175, 2174–2183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Czuczman, M.; Leonard, J.; Jung, S.; Johnson, J.; Hsi, E.; Byrd, J.; Cheson, B. Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Ann. Oncol. 2012, 23, 2356–2362. [Google Scholar] [CrossRef] [PubMed]
  206. Baritaki, S.; Suzuki, E.; Vega, M.; Ho, S.; Hariharan, K.; Bonavida, B. Galiximab Sensitizes Malignant Human B Cell Lines to Apoptosis by Chemotherapeutic Drugs. Blood 2007, 110, 3591. [Google Scholar] [CrossRef]
  207. Martinez-Paniagua, M.A.; Vega, M.I.; Huerta-Yepez, S.; Baritaki, S.; Vega, G.G.; Hariharan, K.; Bonavida, B. Galiximab Signals B-NHL Cells and Inhibits the Activities of NF-κB–Induced YY1-and Snail-Resistant Factors: Mechanism of Sensitization to Apoptosis by Chemoimmunotherapeutic Drugs. Mol. Cancer Ther. 2012, 11, 572–581. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  208. Peng, Y.; Croce, C.M. The role of MicroRNAs in human cancer. Signal Transduct. Target Ther. 2016, 1, 15004. [Google Scholar] [CrossRef] [Green Version]
  209. Entezari, M.; Taheriazam, A.; Orouei, S.; Fallah, S.; Sanaei, A.; Hejazi, E.S.; Kakavand, A.; Rezaei, S.; Heidari, H.; Behroozaghdam, M.; et al. LncRNA-miRNA axis in tumor progression and therapy response: An emphasis on molecular interactions and therapeutic interventions. Biomed. Pharmacother. 2022, 154, 113609. [Google Scholar] [CrossRef] [PubMed]
  210. Reda El Sayed, S.; Cristante, J.; Guyon, L.; Denis, J.; Chabre, O.; Cherradi, N. MicroRNA therapeutics in cancer: Current advances and challenges. Cancers 2021, 13, 2680. [Google Scholar] [CrossRef]
  211. Zhang, Y.; He, S.; Mei, R.; Kang, Y.; Duan, J.; Wei, R.; Xiang, C.; Wu, Y.; Lu, X.; Cai, Z.; et al. miR-29a suppresses IL-13-induced cell invasion by inhibiting YY1 in the AKT pathway in lung adenocarcinoma A549 cells. Oncol. Rep. 2018, 39, 2613–2623. [Google Scholar] [CrossRef] [Green Version]
  212. Huang, T.; Wang, G.; Yang, L.; Peng, B.; Wen, Y.; Ding, G.; Wang, Z. MiR-186 inhibits proliferation, migration, and invasion of non-small cell lung cancer cells by downregulating Yin Yang 1. Cancer Biomark. 2017, 21, 221–228. [Google Scholar] [CrossRef] [PubMed]
  213. Zhou, W.-Y.; Chen, J.-C.; Jiao, T.-T.; Hui, N.; Qi, X. MicroRNA-181 targets Yin Yang 1 expression and inhibits cervical cancer progression. Mol. Med. Rep. 2015, 11, 4541–4546. [Google Scholar] [CrossRef] [Green Version]
  214. Chen, Z.; Han, S.; Huang, W.; Wu, J.; Liu, Y.; Cai, S.; He, Y.; Wu, S.; Song, W. MicroRNA-215 suppresses cell proliferation, migration and invasion of colon cancer by repressing Yin-Yang 1. Biochem. Biophys. Res. Commun. 2016, 479, 482–488. [Google Scholar] [CrossRef] [PubMed]
  215. Nie, J.; Ge, X.I.N.; Geng, Y.; Cao, H.A.N.; Zhu, W.E.I.; Jiao, Y.; Wu, J.; Zhou, J.; Cao, J. miR-34a inhibits the migration and invasion of esophageal squamous cell carcinoma by targeting Yin Yang-1. Oncol. Rep. 2015, 34, 311–317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  216. Wang, A.-M.; Huang, T.-T.; Hsu, K.-W.; Huang, K.-H.; Fang, W.-L.; Yang, M.-H.; Lo, S.-S.; Chi, C.-W.; Lin, J.-J.; Yeh, T.-S. Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis. Oncotarget 2014, 5, 5002–5016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  217. Xia, B.; Li, H.; Yang, S.; Liu, T.; Lou, G. MiR-381 inhibits epithelial ovarian cancer malignancy via YY1 suppression. Tumor Biol. 2016, 37, 9157–9167. [Google Scholar] [CrossRef] [PubMed]
  218. Zhang, Y.; Sun, Z.; Zhang, Y.; Fu, T.; Liu, C.; Liu, Y.; Lin, Y. The microRNA-635 suppresses tumorigenesis in non-small cell lung cancer. Biomed. Pharmacother. 2016, 84, 1274–1281. [Google Scholar] [CrossRef]
  219. Liang, F.; Fu, X.; Wang, L. miR-5590-3p-YY1 feedback loop promotes the proliferation and migration of triple-negative breast cancer cells. J. Cell. Biochem. 2019, 120, 18415–18424. [Google Scholar] [CrossRef]
  220. Gao, Y.; Sun, L.; Wu, Z.; Xuan, C.; Zhang, J.; You, Y.; Chen, X. miR-218 inhibits the proliferation of human glioma cells through downregulation of Yin Yang 1. Mol. Med. Rep. 2018, 17, 1926–1932. [Google Scholar] [CrossRef]
  221. Zhou, G.; Han, F.; Shi, Z.; Yu, L.; Li, X.; Yu, C.; Shen, C.; Wan, D.; Zhu, X.; Li, R. DNMT3A-mediated down-regulation of microRNA-105 promotes gastric cancer cell proliferation. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 3377–3383. [Google Scholar]
  222. Jia, B.; Liu, W.; Gu, J.; Wang, J.; Lv, W.; Zhang, W.; Hao, Q.; Pang, Z.; Mu, N.; Zhang, W.; et al. MiR-7-5p suppresses stemness and enhances temozolomide sensitivity of drug-resistant glioblastoma cells by targeting Yin Yang 1. Exp. Cell Res. 2019, 375, 73–81. [Google Scholar] [CrossRef] [PubMed]
  223. Su, H.; Liu, L.; Zhang, Y.; Wang, J.; Zhao, Y. Long noncoding RNA NPCCAT1 promotes nasopharyngeal carcinoma progression via upregulating YY1. Biochimie 2019, 157, 184–194. [Google Scholar] [CrossRef] [PubMed]
  224. Rong, D.; Dong, Q.; Qu, H.; Deng, X.; Gao, F.; Li, Q.; Sun, P. m(6)A-induced LINC00958 promotes breast cancer tumorigenesis via the miR-378a-3p/YY1 axis. Cell Death Discov. 2021, 7, 27. [Google Scholar] [CrossRef]
  225. Cheng, Z.; Liu, G.; Huang, C.; Zhao, X. KLF5 activates lncRNA DANCR and inhibits cancer cell autophagy accelerating gastric cancer progression. NPJ Genom. Med. 2021, 6, 75. [Google Scholar] [CrossRef] [PubMed]
  226. Zhou, Y.; Wang, Y.; Lin, M.; Wu, D.; Zhao, M. LncRNA HOTAIR promotes proliferation and inhibits apoptosis by sponging miR-214-3p in HPV16 positive cervical cancer cells. Cancer Cell Int. 2021, 21, 400. [Google Scholar] [CrossRef]
  227. Kulkarni, J.A.; Witzigmann, D.; Thomson, S.B.; Chen, S.; Leavitt, B.R.; Cullis, P.R.; van der Meel, R. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol. 2021, 16, 630–643. [Google Scholar] [CrossRef]
  228. Hu, B.; Zhong, L.; Weng, Y.; Peng, L.; Huang, Y.; Zhao, Y.; Liang, X.-J. Therapeutic siRNA: State of the art. Signal Transduct. Target Ther. 2020, 5, 101. [Google Scholar] [CrossRef]
  229. Cuciniello, R.; Filosa, S.; Crispi, S. Novel approaches in cancer treatment: Preclinical and clinical development of small non-coding RNA therapeutics. J. Exp. Clin. Cancer Res. 2021, 40, 383. [Google Scholar] [CrossRef]
  230. Kao, S.C.; Fulham, M.; Wong, K.; Cooper, W.; Brahmbhatt, H.; MacDiarmid, J.; Pattison, S.; Sagong, J.O.; Huynh, Y.; Leslie, F.; et al. A significant metabolic and radiological response after a novel targeted microRNA-based treatment approach in malignant pleural mesothelioma. Am. J. Respir. Crit. Care Med. 2015, 191, 1467–1469. [Google Scholar] [CrossRef] [Green Version]
  231. Querfeld, C.; Pacheco, T.; Foss, F.M.; Halwani, A.S.; Porcu, P.; Seto, A.G.; Ruckman, J.; Landry, M.L.; Jackson, A.L.; Pestano, L.A.; et al. Preliminary Results of a Phase 1 Trial Evaluating MRG-106, a Synthetic microRNA Antagonist (LNA antimiR) of microRNA-155, in Patients with CTCL. Blood 2016, 128, 1829. [Google Scholar] [CrossRef]
  232. Winkle, M.; El-Daly, S.M.; Fabbri, M.; Calin, G.A. Noncoding RNA therapeutics—Challenges and potential solutions. Nat. Rev. Drug Discov. 2021, 20, 629–651. [Google Scholar] [CrossRef]
  233. Chen, Y.; Gao, D.-Y.; Huang, L. In vivo delivery of miRNAs for cancer therapy: Challenges and strategies. Adv. Drug Deliv. Rev. 2015, 81, 128–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  234. Kim, H.J.; Kim, A.; Miyata, K.; Kataoka, K. Recent progress in development of siRNA delivery vehicles for cancer therapy. Adv. Drug Deliv. Rev. 2016, 104, 61–77. [Google Scholar] [CrossRef] [Green Version]
  235. Yao, Y.; Zhou, Y.; Liu, L.; Xu, Y.; Chen, Q.; Wang, Y.; Wu, S.; Deng, Y.; Zhang, J.; Shao, A. Nanoparticle-based drug delivery in cancer therapy and its role in overcoming drug resistance. Front. Mol. Biosci. 2020, 7, 193. [Google Scholar] [CrossRef] [PubMed]
  236. Menon, A.; Abd-Aziz, N.; Khalid, K.; Poh, C.L.; Naidu, R. miRNA: A promising therapeutic target in cancer. Int. J. Mol. Sci. 2022, 23, 11502. [Google Scholar] [CrossRef]
  237. Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009, 324, 1029–1033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  238. Meliala, I.T.S.; Hosea, R.; Kasim, V.; Wu, S. Yin and Yang of YY1 regulation on tumor metabolic reprogramming. In YY1 in the Control of the Pathogenesis and Drug Resistance of Cancer; Elsevier: Amsterdam, The Netherlands, 2021; pp. 79–99. [Google Scholar]
  239. Yap, T.A.; Parkes, E.E.; Peng, W.; Moyers, J.T.; Curran, M.A.; Tawbi, H.A. Development of Immunotherapy Combination Strategies in CancerImmunotherapy Combination Strategies in Cancer. Cancer Discov. 2021, 11, 1368–1397. [Google Scholar] [CrossRef] [PubMed]
  240. Nakanishi, Y.; Nakatsuji, M.; Seno, H.; Ishizu, S.; Akitake-Kawano, R.; Kanda, K.; Ueo, T.; Komekado, H.; Kawada, M.; Minami, M.; et al. COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in ApcMin/+ mouse polyps. Carcinogenesis 2011, 32, 1333–1339. [Google Scholar] [CrossRef] [Green Version]
  241. Balkhi, M.Y.; Wittmann, G.; Xiong, F.; Junghans, R.P. YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted, Chronically Stimulated Human T Cells. iScience 2018, 2, 105–122. [Google Scholar] [CrossRef] [Green Version]
  242. Robert, C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat. Commun. 2020, 11, 3801. [Google Scholar] [CrossRef]
  243. Karasarides, M.; Cogdill, A.P.; Robbins, P.B.; Bowden, M.; Burton, E.M.; Butterfield, L.H.; Cesano, A.; Hammer, C.; Haymaker, C.L.; Horak, C.E. Hallmarks of Resistance to Immune-Checkpoint Inhibitors. Cancer Immunol. Res. 2022, 10, 372–383. [Google Scholar] [CrossRef] [PubMed]
  244. Tang, H.; Liu, Y.; Wang, C.; Zheng, H.; Chen, Y.; Liu, W.; Chen, X.; Zhang, J.; Chen, H.; Yang, Y. Inhibition of COX-2 and EGFR by melafolone improves anti-PD-1 therapy through vascular normalization and PD-L1 downregulation in lung cancer. J. Pharmacol. Exp. Ther. 2019, 368, 401–413. [Google Scholar] [CrossRef] [Green Version]
  245. Lemoine, J.; Ruella, M.; Houot, R. Born to survive: How cancer cells resist CAR T cell therapy. J. Hematol. Oncol. 2021, 14, 199. [Google Scholar] [CrossRef]
  246. Hirayama, A.V.; Gauthier, J.; Hay, K.A.; Sheih, A.; Cherian, S.; Chen, X.; Pender, B.S.; Hawkins, R.M.; Vakil, A.; Steinmetz, R.N. Efficacy and toxicity of JCAR014 in combination with durvalumab for the treatment of patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Blood 2018, 132, 1680. [Google Scholar] [CrossRef]
  247. Wang, C.; Shi, F.; Liu, Y.; Zhang, Y.; Dong, L.; Li, X.; Tong, C.; Wang, Y.; Su, L.; Nie, J. Anti-PD-1 antibodies as a salvage therapy for patients with diffuse large B cell lymphoma who progressed/relapsed after CART19/20 therapy. J. Hematol. Oncol. 2021, 14, 106. [Google Scholar] [CrossRef] [PubMed]
  248. Wang, Z.; Li, N.; Feng, K.; Chen, M.; Zhang, Y.; Liu, Y.; Yang, Q.; Nie, J.; Tang, N.; Zhang, X. Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors. Cell. Mol. Immunol. 2021, 18, 2188–2198. [Google Scholar] [CrossRef]
  249. Rafiq, S.; Yeku, O.O.; Jackson, H.J.; Purdon, T.J.; Van Leeuwen, D.G.; Drakes, D.J.; Song, M.; Miele, M.M.; Li, Z.; Wang, P. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 2018, 36, 847–856. [Google Scholar] [CrossRef]
  250. Nebbioso, A.; Tambaro, F.P.; Dell’Aversana, C.; Altucci, L. Cancer epigenetics: Moving forward. PLoS Genet. 2018, 14, e1007362. [Google Scholar] [CrossRef] [Green Version]
  251. Atchison, L.; Ghias, A.; Wilkinson, F.; Bonini, N.; Atchison, M.L. Transcription factor YY1 functions as a PcG protein in vivo. EMBO J. 2003, 22, 1347–1358. [Google Scholar] [CrossRef]
  252. Wilkinson, F.H.; Park, K.; Atchison, M.L. Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc. Natl. Acad. Sci. USA 2006, 103, 19296–19301. [Google Scholar] [CrossRef]
  253. Yang, W.-M.; Yao, Y.-L.; Sun, J.-M.; Davie, J.R.; Seto, E. Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family. J. Biol. Chem. 1997, 272, 28001–28007. [Google Scholar] [CrossRef] [Green Version]
  254. Lee, J.-S.; Galvin, K.M.; See, R.H.; Eckner, R.; Livingston, D.; Moran, E.; Shi, Y. Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300. Genes Dev. 1995, 9, 1188–1198. [Google Scholar] [CrossRef] [Green Version]
  255. Rezai-Zadeh, N.; Zhang, X.; Namour, F.; Fejer, G.; Wen, Y.-D.; Yao, Y.-L.; Gyory, I.; Wright, K.; Seto, E. Targeted recruitment of a histone H4-specific methyltransferase by the transcription factor YY1. Genes Dev. 2003, 17, 1019–1029. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  256. Cai, Y.; Jin, J.; Yao, T.; Gottschalk, A.J.; Swanson, S.K.; Wu, S.; Shi, Y.; Washburn, M.P.; Florens, L.; Conaway, R.C. YY1 functions with INO80 to activate transcription. Nat. Struct. Mol. Biol. 2007, 14, 872–874. [Google Scholar] [CrossRef] [PubMed]
  257. Wang, J.; Wu, X.; Wei, C.; Huang, X.; Ma, Q.; Huang, X.; Faiola, F.; Guallar, D.; Fidalgo, M.; Huang, T. YY1 positively regulates transcription by targeting promoters and super-enhancers through the BAF complex in embryonic stem cells. Stem Cell Rep. 2018, 10, 1324–1339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  258. Deng, S.; Feng, Y.; Pauklin, S. 3D chromatin architecture and transcription regulation in cancer. J. Hematol. Oncol. 2022, 15, 49. [Google Scholar] [CrossRef]
  259. Schwalie, P.C.; Ward, M.C.; Cain, C.E.; Faure, A.J.; Gilad, Y.; Odom, D.T.; Flicek, P. Co-binding by YY1 identifies the transcriptionally active, highly conserved set of CTCF-bound regions in primate genomes. Genome Biol. 2013, 14, R148. [Google Scholar] [CrossRef] [Green Version]
  260. Pan, X.; Papasani, M.; Hao, Y.; Calamito, M.; Wei, F.; Quinn, W.J.; Basu, A.; Wang, J.; Hodawadekar, S.; Zaprazna, K. YY1 controls Igκ repertoire and B-cell development, and localizes with condensin on the Igκ locus. EMBO J. 2013, 32, 1168–1182. [Google Scholar] [CrossRef] [Green Version]
  261. Morris, E.C.; Neelapu, S.S.; Giavridis, T.; Sadelain, M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat. Rev. Immunol. 2022, 22, 85–96. [Google Scholar] [CrossRef]
  262. Drago, J.Z.; Modi, S.; Chandarlapaty, S. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat. Rev. Clin. Oncol. 2021, 18, 327–344. [Google Scholar] [CrossRef]
  263. Li, L.; Li, Y.; Timothy Sembiring Meliala, I.; Kasim, V.; Wu, S. Biological roles of Yin Yang 2: Its implications in physiological and pathological events. J. Cell. Mol. Med. 2020, 24, 12886–12899. [Google Scholar] [CrossRef]
  264. Nguyen, N.; Zhang, X.; Olashaw, N.; Seto, E. Molecular Cloning and Functional Characterization of the Transcription Factor YY2. J. Biol. Chem. 2004, 279, 25927–25934. [Google Scholar] [CrossRef] [Green Version]
  265. Kasim, V.; Xie, Y.-D.; Wang, H.-M.; Huang, C.; Yan, X.-S.; Nian, W.-Q.; Zheng, X.-D.; Miyagishi, M.; Wu, S.-R. Transcription factor Yin Yang 2 is a novel regulator of the p53/p21 axis. Oncotarget 2017, 8, 54694–54707. [Google Scholar] [CrossRef] [Green Version]
  266. Chen, L.; Shioda, T.; Coser, K.R.; Lynch, M.C.; Yang, C.; Schmidt, E.V. Genome-wide analysis of YY2 versus YY1 target genes. Nucleic Acids Res. 2010, 38, 4011–4026. [Google Scholar] [CrossRef] [Green Version]
  267. Figiel, M.; Łakomska, J.; Miłek, P.; Dziedzicka-Wasylewska, M.; Górecki, A. The transcription factor YY2 has less momentous properties of an intrinsically disordered protein than its paralog YY1. FEBS Lett. 2019, 593, 1787–1798. [Google Scholar] [CrossRef]
  268. Kaufhold, S.; Aziz, N.; Bonavida, B. The forgotten YY2 in reported YY1 expression levels in human cancers. Crit. Rev. Oncog. 2017, 22, 63–73. [Google Scholar] [CrossRef]
  269. Jin, H.; Wang, L.; Bernards, R. Rational combinations of targeted cancer therapies: Background, advances and challenges. Nat. Rev. Drug Discov. 2023, 22, 213–234. [Google Scholar] [CrossRef]
  270. Hinshaw, D.C.; Shevde, L.A. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019, 79, 4557–4566. [Google Scholar] [CrossRef] [Green Version]
  271. Baghban, R.; Roshangar, L.; Jahanban-Esfahlan, R.; Seidi, K.; Ebrahimi-Kalan, A.; Jaymand, M.; Kolahian, S.; Javaheri, T.; Zare, P. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun. Signal. 2020, 18, 59. [Google Scholar] [CrossRef] [Green Version]
  272. Turley, S.J.; Cremasco, V.; Astarita, J.L. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol. 2015, 15, 669–682. [Google Scholar] [CrossRef]
  273. Liu, X.; Cao, Z.; Liu, N.; Gao, G.; Du, M.; Wang, Y.; Cheng, B.; Zhu, M.; Jia, B.; Pan, L. Kill two birds with one stone: Engineered exosome-mediated delivery of cholesterol modified YY1-siRNA enhances chemoradiotherapy sensitivity of glioblastoma. Front. Pharmacol. 2022, 13, 975291. [Google Scholar] [CrossRef]
  274. Gambardella, V.; Tarazona, N.; Cejalvo, J.M.; Lombardi, P.; Huerta, M.; Roselló, S.; Fleitas, T.; Roda, D.; Cervantes, A. Personalized medicine: Recent progress in cancer therapy. Cancers 2020, 12, 1009. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  275. Ren, C.; Zhang, G.; Han, F.; Fu, S.; Cao, Y.; Zhang, F.; Zhang, Q.; Meslamani, J.; Xu, Y.; Ji, D.; et al. Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth. Proc. Natl. Acad. Sci. USA 2018, 115, 7949–7954. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  276. Zhang, C.; Shen, L.; Zhu, Y.; Xu, R.; Deng, Z.; Liu, X.; Ding, Y.; Wang, C.; Shi, Y.; Bei, L.; et al. KDM6A promotes imatinib resistance through YY1-mediated transcriptional upregulation of TRKA independently of its demethylase activity in chronic myelogenous leukemia. Theranostics 2021, 11, 2691–2705. [Google Scholar] [CrossRef] [PubMed]
  277. Meng, J.; Han, J.; Wang, X.; Wu, T.; Zhang, H.; An, H.; Qin, L.; Sun, Y.; Zhong, W.; Yang, C. Twist1-YY1-p300 complex promotes the malignant progression of HCC through activation of miR-9 by forming phase-separated condensates at super-enhancers and relieved by Metformin. Pharmacol. Res. 2023, 188, 106661. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Schematic diagram illustrating the mechanism of YY1 regulation in tumor drug resistance. YY1 promotes drug resistance through regulation of the DNA repair response, anti-apoptotic proteins, and drug efflux transporters. Bcl-2: B-cell lymphoma-2; Bcl-XL: B-cell lymphoma-extra large; Bim: Bcl-2 interacting mediator of cell death; BRCA1: Breast cancer-associated gene 1; MDR1: multidrug resistance protein 1.
Figure 1. Schematic diagram illustrating the mechanism of YY1 regulation in tumor drug resistance. YY1 promotes drug resistance through regulation of the DNA repair response, anti-apoptotic proteins, and drug efflux transporters. Bcl-2: B-cell lymphoma-2; Bcl-XL: B-cell lymphoma-extra large; Bim: Bcl-2 interacting mediator of cell death; BRCA1: Breast cancer-associated gene 1; MDR1: multidrug resistance protein 1.
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Figure 2. Targeting transcription factor YY1 for antitumor therapy. (A) DETA-NONOate inhibits YY1 binding to the promoter. (B) Betulinic acid inhibits YY1 through cannabinoid-receptor-dependent disruption of microRNA-27a:ZBTB10. (C) JAC1 targets YY1-mediated JWA/p38 signaling to inhibit tumor proliferation. (D) YY1BM inhibits the interaction between YY1 and the androgen receptor, which in turn decreases expression of eEF2K through the AR signaling pathway. (E) Synthetic peptides with the OPB domain disrupt the regulation of YY1 by competitive binding. (F) Antibody-based inhibition of YY1 through inhibition of the NF-κB signaling pathway. (G) Nucleic-acid-based inhibition of YY1. (H) CRISPR/Cas9 genome editing of YY1. (I) Role of YY1 in immunotherapy based on CAR-T cells. AKT: protein kinase B; AR: androgen receptor; BRD2/4: bromodomain-containing protein 2/4; CAR: chimeric antigen receptor; CAR-T cell: chimeric antigen receptor T cell; CB1: cannabinoid receptor 1; CB2: cannabinoid receptor 2; Cas9: CRISPR-associated protein 9; COX-2: cyclooxygenase 2; DETA-NONOate: diethylenetriamine NONOate; EGFR: epidermal growth factor receptor; eEF2K: eukaryotic elongation factor 2 kinase; ErbB2: erb-b2 receptor tyrosine kinase 2; Fas: Fas death receptor; HSF1: heat shock factor 1; IL-2: Interleukin 2; JWA: ADP ribosylation factor like GTPase 6 interacting protein 5 (ARL6IP5); LINC00278: Y-linked long noncoding RNA 278; NO: nitric oxide; OPB: oncoprotein binding domain; PD-1: programmed death 1; PD-L1: programmed death ligand 1; PFKP: phosphofructokinase, platelet; p38: p38 mitogen-activated protein kinase; sgRNA: single guide RNA; TSA: tumor-specific antigen; TRAIL: tumor necrosis factor related apoptosis-inducing ligand; YY1BM: YY1-blocking micropeptide; ZBTB10: zinc-finger and BTB domain containing 10.
Figure 2. Targeting transcription factor YY1 for antitumor therapy. (A) DETA-NONOate inhibits YY1 binding to the promoter. (B) Betulinic acid inhibits YY1 through cannabinoid-receptor-dependent disruption of microRNA-27a:ZBTB10. (C) JAC1 targets YY1-mediated JWA/p38 signaling to inhibit tumor proliferation. (D) YY1BM inhibits the interaction between YY1 and the androgen receptor, which in turn decreases expression of eEF2K through the AR signaling pathway. (E) Synthetic peptides with the OPB domain disrupt the regulation of YY1 by competitive binding. (F) Antibody-based inhibition of YY1 through inhibition of the NF-κB signaling pathway. (G) Nucleic-acid-based inhibition of YY1. (H) CRISPR/Cas9 genome editing of YY1. (I) Role of YY1 in immunotherapy based on CAR-T cells. AKT: protein kinase B; AR: androgen receptor; BRD2/4: bromodomain-containing protein 2/4; CAR: chimeric antigen receptor; CAR-T cell: chimeric antigen receptor T cell; CB1: cannabinoid receptor 1; CB2: cannabinoid receptor 2; Cas9: CRISPR-associated protein 9; COX-2: cyclooxygenase 2; DETA-NONOate: diethylenetriamine NONOate; EGFR: epidermal growth factor receptor; eEF2K: eukaryotic elongation factor 2 kinase; ErbB2: erb-b2 receptor tyrosine kinase 2; Fas: Fas death receptor; HSF1: heat shock factor 1; IL-2: Interleukin 2; JWA: ADP ribosylation factor like GTPase 6 interacting protein 5 (ARL6IP5); LINC00278: Y-linked long noncoding RNA 278; NO: nitric oxide; OPB: oncoprotein binding domain; PD-1: programmed death 1; PD-L1: programmed death ligand 1; PFKP: phosphofructokinase, platelet; p38: p38 mitogen-activated protein kinase; sgRNA: single guide RNA; TSA: tumor-specific antigen; TRAIL: tumor necrosis factor related apoptosis-inducing ligand; YY1BM: YY1-blocking micropeptide; ZBTB10: zinc-finger and BTB domain containing 10.
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Figure 3. Overview of the current strategies and potential of targeting YY1 in antitumor therapy.
Figure 3. Overview of the current strategies and potential of targeting YY1 in antitumor therapy.
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Table
Table 1. Expression of YY1 in various cancers.
Table 1. Expression of YY1 in various cancers.
Cancer Types YY1 Expression LevelPrognosis Refs.
Bladder Upregulated Poor [33,34]
BreastUpregulatedPoor[35]
Cervical Upregulated Poor[36,37]
Colon Upregulated Poor[38,39,40,41]
Esophageal Upregulated Poor [42]
Gastric Upregulated Poor [43,44]
Glioma Upregulated Poor[45,46,47]
Hodgkin lymphoma Upregulated n/a [48]
Leukemia Upregulated Poor [49,50,51]
Liver Upregulated Poor [52]
Lung Upregulated Poor[27,53]
Melanoma Upregulated Poor[51,54,55,56]
Multiple myeloma Upregulated Poor[57]
Nasopharynx Downregulated Good[58]
Non-Hodgkin lymphoma Upregulated Poor[59,60,61,62]
Downregulated Good [63]
Osteosarcoma Upregulated Poor [32]
Ovarian Upregulated Poor[23,64,65]
Pancreatic Upregulated Poor[66]
UpregulatedPoor[67]
Renal Upregulated Poor[68]
Sarcoma Upregulated n/a[69]
Upregulated Poor [32]
Testicular seminoma Upregulated Poor [70,71]
Thyroid Upregulated Poor[72,73,74]
n/a: not available.
Table
Table 2. Transcription factor YY1 regulates the hallmarks of cancer.
Table 2. Transcription factor YY1 regulates the hallmarks of cancer.
TargetPathwayHallmarksRefs.
AKTYY1/mTORC2/AKTEvading apoptosis; limitless replicative potential; sustained angiogenesis; tissue invasion and metastasis [74,94]
APCmiR-193a-5p/YY1/APCLimitless replicative potential [95]
Atg5YY1/TFEB/Atg5-Atg12-Atg16Evading apoptosis (by evading autophagy) [56]
Beclin1YY1/TFEB/Beclin1Evading apoptosis (by evading autophagy) [56]
BimYY1/RelA/BimEvading apoptosis; limitless replicative potential [96]
CDKN2AYY1/HDACs/CDKN2AEvading apoptosis [97,98]
CDKN3YY1/CDKN3/MdM2/p53/p21Limitless replicative potential; tissue invasion and metastasis [99]
c-MycYY1/c-MycDeregulated metabolism; evading apoptosis; genome instability; limitless replicative potential; tissue invasion and metastasis [87,100]
COX2YY1/COX2/PGEvading immune system [101,102]
CXCR4CXCR4/YY1/VEGFSustained angiogenesis; tissue invasion and metastasis [103]
CXCR4SDF-1α/CXCR4/YY1/let-7aEvading apoptosis; evading immune system [104]
DEKYY1/DEK/HIF-1α/VEGFSustained angiogenesis [105]
DEKYY1/NF-Y/DEKLimitless replicative potential [106]
DR5YY1/DR5/TRAIL/NF-κBEvading apoptosis; evading immune system [107,108]
DTDSTNF-κB/YY1/PRC2-EZH2/
DTDST		Evading immune system; limitless replicative potential; tissue invasion and metastasis [109]
CDH1YY1-PRMT7-HDAC3/H3K4me3/CDH1Tissue invasion and metastasis [110]
EGFRmir-34a/YY1/EGFRLimitless replicative potential [111]
EGFRMCT1/YY1/EGFR/MnSODDeregulate metabolism; evading apoptosis [112]
ERBB2YY1/AP-2α/ERBB2Sustained angiogenesis; tissue invasion and metastasis [113]
FasmiR27a/ZBTB10/Sp/YY1/
ERBB2		Limitless proliferative potential [75]
G6PDYY1/G6PD/PPP/r5pDeregulated metabolism [85]
GLUT3YY1/GLUT3Deregulated metabolism; limitless replicative potential [91]
HIF-1αYY1/HIF-1α/GLUT1-GLUT3Deregulated metabolism; evading apoptosis [114]
HIF-1αYY1/HIF-1α/VEGF & TGF-αSustained angiogenesis; tissue invasion and metastasis [84,103]
HIF-1αYY1/HIF-1α/CA9Evading immune system; tissue invasion and metastasis [84,115,116]
HIF-1αYY1/HIF-1α/PGKEvading apoptosis; deregulated metabolism; sustaining proliferative signaling [84,117]
hnRNPMYY1/hnRNPM/CD44Tissue invasion and metastasis [118]
HPV18YY1-CTCF/HPV18Insensitivity to anti-growth signals; limitless replicative potential [119]
IL6YY1/IL6/STAT3/PD-L1Evading immune system [22]
KLF4YY1/KLF4/p53 Evading apoptosis [120]
KLF5YY1/KLF4/p21Limitless replicative potential [120]
KLF6YY1/KLF4/c-MycDeregulated metabolism; evading apoptosis; genome instability; limitless replicative potential; tissue invasion and metastasis [87,120]
KLF7YY1/KLF4/cyclin D2Limitless replicative potential [120]
MAP1LC3BYY1/TFEB/MAP1LC3BEvading apoptosis [56]
miR-125aRYBP/YY1/pri-miR-125aEvading apoptosis, evading immune system [121]
miR-195miR-195/Smurf2YY1/VEGFA/
Snail1		Tissue invasion and metastasis [122]
miR-30aYY1/miR-30a/ATG5 & Beclin1Evading apoptosis [123]
miR-372YY1/mIR-372/SQSTM1Evading apoptosis [124]
miR-9YY1/EZH2/H3K27me3/miR9/
NF-κB1		Evading apoptosis; tissue invasion and metastasis [30]
p21YY1/BCCIP/p53re/p21Evading apoptosis; limitless replicative potential [90]
p53YY1/BCCIP/p53re/p21Evading apoptosis; limitless replicative potential [90]
p53YY1/MDM2/p53Evading apoptosis [89]
p53p14ARF/YY1/Hdm2/p53Evading apoptosis; insensitivity to anti-growth signals [88]
p53YY1/TIGAR/PDK2/PFK-1Deregulated metabolism; evading apoptosis [125]
p53YY1/p300/MDM2/p53Evading apoptosis [88]
p53Smurf2/YY1/p53Evading apoptosis; evading immune system [126,127]
p73YY1/E2F1/p73Evading apoptosis; insensitivity to anti-growth signals [128]
PGC-1βYY1/PGC-1β/MCAD & LCADDeregulated metabolism [92]
RelBYY1/RelB/p65 & p50Evading apoptosis; evading immune system [46]
RYBPYY1/miR-9/RYBP/SP1Evading apoptosis; insensitivity to anti-growth signals; tissue invasion and metastasis [129]
RYBPRYBP/YY1/E2F6/Mae1 or Staq3 or Smc1βInsensitivity to anti-growth signals; limitless replicative potential [130]
RYBPRYBP/YY1/E2F2 or E2F3/CDC7Genome instability; insensitivity to anti-growth signals; limitless replicative potential [130]
ST6GalNAc6YY1/PRC2/EZH2/H3K27me3/
DTDST/ST6GalNAc6		Evading immune system; genome instability [97,109]
TPPPYY1/TPPP/p38/MAPKEvading apoptosis; sustained angiogenesis; tissue invasion and metastasis [131]
TPPPYY1/TPPP/PI3K/AKTSustained angiogenesis; tissue invasion and metastasis [131]
VEGFCXCR4/YY1/VEGFSustained angiogenesis; tissue invasion and metastasis [103]
VEGFYY1/VEGFA/VEGFR2Evading apoptosis; sustained angiogenesis [132]
VEGFBCXCR4/YY1/VEGFBSustained angiogenesis; tissue invasion and metastasis [103]
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Hosea, R.; Hillary, S.; Wu, S.; Kasim, V. Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions. Cancers 2023, 15, 3506. https://doi.org/10.3390/cancers15133506

AMA Style

Hosea R, Hillary S, Wu S, Kasim V. Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions. Cancers. 2023; 15(13):3506. https://doi.org/10.3390/cancers15133506

Chicago/Turabian Style

Hosea, Rendy, Sharon Hillary, Shourong Wu, and Vivi Kasim. 2023. "Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions" Cancers 15, no. 13: 3506. https://doi.org/10.3390/cancers15133506

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