Search Results (125)

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy caused by persistent infection with human T-cell leukemia virus type 1 (HTLV-1). ATLL remains difficult to treat despite intensive chemotherapy, antiviral therapy, and hematopoietic stem cell transplantation. The limited durability of current treatment strategies highlights the need for mechanism-based therapeutic approaches. Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that regulates transcription, RNA splicing, DNA damage responses, and immune signaling through symmetric dimethylation of histone and non-histone substrates. PRMT5 is frequently overexpressed across hematologic and solid tumors. Preclinical studies indicate that PRMT5 expression is elevated during HTLV-1-mediated T-cell transformation and that pharmacologic inhibition of PRMT5 selectively impairs the survival and transformation of infected T cells in vitro and in vivo. In this review, we highlight the current understanding of PRMT5 biology in cancer, summarize preclinical studies supporting PRMT5 as a therapeutic target in ATLL, and discuss key challenges to future clinical translation. We also discuss emerging approaches such as rational combination therapies and tumor-selective PRMT5 inhibitors as potential paths toward treatment for ATLL. Full article

The MTAP (methylthioadenosine phosphorylase) gene, located on chromosome 9p21, plays a crucial role in the methionine salvage pathway and is frequently co-deleted with CDKN2A in various malignancies. Loss of MTAP expression leads to the accumulation of methylthioadenosine (MTA), which selectively inhibits protein arginine methyltransferase 5 (PRMT5) and creates a unique metabolic vulnerability in MTAP-deficient tumors. These alterations have emerged as promising therapeutic targets in precision oncology. Recent advances highlight the potential of exploiting MTAP loss through synthetic lethality approaches using PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibitors. Preclinical and early clinical data indicate that targeting these pathways can selectively impair tumor growth while sparing MTAP-proficient cells. Moreover, MTAP deletion has been associated with specific molecular and immunologic profiles that may influence treatment response and tumor microenvironment characteristics. This review summarizes current knowledge on the biological functions of MTAP, the mechanisms linking its loss to oncogenesis, and the evolving landscape of therapeutic strategies targeting MTAP-deficient cancers. Understanding these molecular dependencies offers novel opportunities for the development of precision-based therapies across diverse tumor types. Full article

PRMT5, a type II methyltransferase catalyzing symmetric dimethylation of arginine residues, has emerged as a promising therapeutic target in various cancers. However, the precise mechanism by which PRMT5 mediated the tumor immune microenvironment, particularly CD8⁺ T cell recruitment in cervical cancer remains elusive. Analysis of data from The Cancer Genome Atlas (TCGA) revealed elevated PRMT5 mRNA levels in cervical cancer tissues, which correlated with reduced immune cell infiltration and poorer patient prognosis. To further investigate the role of PRMT5 in tumor development, a CD8 knockout (KO) mouse tumor model was utilized. Significant inhibition of tumor growth was observed in cervical cancer using a mouse model lacking PRMT5. Notably, this antitumor effect was attenuated in CD8 KO mice lacking functional CD8⁺ T cells. Mechanistically, RNA sequencing (RNA-seq) analysis was conducted to explore how PRMT5 regulates immune cell recruitment. Disruption of PRMT5 was found to increase the secretion of chemokine CXCL10 by tumor cells. CXCL10 binds to its receptor CXCR3, thereby recruiting T cells to the tumor. Furthermore, in CXCR3 KO mice, PRMT5 knockdown failed to enhance T cell infiltration into tumors. These findings indicate that PRMT5 knockdown promotes CD8⁺ T cell recruitment to the tumor microenvironment via CXCL10 signaling. Furthermore, the therapeutic efficacy of the selective PRMT5 inhibitor EPZ015666 was evaluated in a cervical cancer xenograft mouse model. Treatment with EPZ015666 effectively suppressed tumor growth. In summary, these findings elucidate a novel mechanism whereby PRMT5 depletion in cervical cancer cells triggers a CXCL10-mediated chemotactic response, enhancing CD8⁺ T cell infiltration and restricting tumor progression. Thus, our study provides compelling evidence supporting the potential targeting of PRMT5 as a viable immunotherapeutic strategy for cervical cancer. Full article

Pulmonary carcinoma remains a highly aggressive malignancy driven by complex signaling and epigenetic dysregulation. This study investigates a novel oncogenic pathway involving the Mg^2+/Mn²⁺-dependent protein phosphatase 1B PPM1B/myosin phosphatase (MP)/protein arginine methyltransferase 5 (PRMT5) axis, which promotes carcinogenesis by symmetrically dimethylating histone H2A and suppressing tumor suppressor genes. We hypothesized that loss of PPM1B would activate this pathway and drive tumorigenesis. Western blotting, PCR, and immunohistochemistry revealed a significant reduction in PPM1B expression in both squamous cell carcinoma (SCC) and human lung adenocarcinoma (ADC) compared to normal lung tissues, which correlated with worse patient survival. Despite an increase in total MYPT1, the regulatory subunit of MP, its inhibitory phosphorylation at Thr853 was significantly elevated in both tumor types. The inactivation of MP corresponded with a significant increase in the activating phosphorylation of PRMT5 at Thr80, especially in SCC, which was linked to a particularly poor prognosis. Downstream, this resulted in a dramatic elevation in the symmetric dimethylation of histone H2A, leading to decreased expression of retinoblastoma protein. Our findings demonstrate that decreased PPM1B expression drives the oncogenic activation of the MP/PRMT5 axis. This mechanism contributes to the aggressive nature of SCC, establishing PPM1B as a promising prognostic marker in lung cancer. Full article

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. Recent breakthroughs in research are highlighting the complex genetic and epigenetic alterations driving CRC progression. Among these, the ERK1/2 and PI3K pathways are central regulators of cellular proliferation, survival, and differentiation. The overactivation of these pathways is frequently observed in cancer and is associated with poor patient prognosis. Protein Arginine Methyltransferase 5 (PRMT5), a key epigenetic regulator, has been implicated in modulating the ERK1/2 and PI3K pathways in cancer. Previous studies, including those from our own group, are starting to suggest that targeting PRMT5 and the ERK1/2 and PI3K pathways may offer therapeutic benefits. Thus, we sought to provide further evidence of the relationship between PRMT5 and the ERK1/2 and PI3K pathways in CRC. Using patient tumor gene expression data and protein–protein interaction networks, we provide further evidence that PRMT5 is positively correlated with, and interacts with, the ERK1/2 and PI3K pathways in CRC. These findings are significant, as they further strengthen the case for the urgent need of additional research into therapeutic strategies targeting PRMT5 and the ERK1/2 and PI3K pathways in CRC. Full article

Post-translational modifications (PTMs) expand the structural diversity of proteins beyond the standard amino acids, influencing protein-protein interactions. Protein methylation, a prevalent PTM, involves the transfer of methyl groups from S-adenosylmethionine (SAM) to lysine and arginine residues. Arginine methylation is catalyzed by the Protein Arginine Methyltransferase (PRMT) family to yield mono- and dimethylarginine forms. PRMT1, the isozyme responsible for the majority of asymmetric dimethylation (ADMA) is implicated in various diseases, including cancer. Here, we report the synthesis and screening of a second-generation peptide library to identify novel PRMT1 substrates. The library, based on histone peptides, incorporated varying sequences of amino acids, facilitating substrate specificity studies. Screening identified 7 peptide sequences as exceptional PRMT1 substrates, which were confirmed by kinetic analysis. Consensus sequences revealed key recognition elements for PRMT1 catalysis, suggesting roles for small non-polar side chains and specific residues near the substrate arginine. Furthermore, we developed a peptide-based PRMT1 inhibitor by substituting the substrate arginine with a chloroacetamidine warhead. The inhibitor exhibited sub-micromolar inhibitory potency against PRMT1, surpassing previous peptide-based inhibitors. Our findings contribute to understanding PRMT1 substrate specificity and provide a scaffold for developing potent inhibitors targeting PRMT1 in diseases, including cancer. Full article

Tacrolimus-induced chronic nephrotoxicity (TACN) represents a major barrier to long-term graft survival in kidney transplantation, yet its molecular pathogenesis remains incompletely understood. We have previously reported metabolic abnormalities, including carnitine deficiency, nicotinamide adenine dinucleotide depletion, and elevated asymmetric dimethyl arginine (ADMA), in TACN. To identify upstream regulators associated with these metabolic disturbances, we conducted a comprehensive trans-omic analysis, integrating transcriptomics and proteomics of kidney tissues from male ICR mice with TACN (n = 5/group). Differentially expressed genes and proteins were subjected to functional enrichment and transcription factor binding motif analyses, followed by upstream master regulator identification using the Genome Enhancer platform. A total of 785 genes and 2472 proteins were differentially expressed, with partially discordant regulation between transcriptomic and proteomic profiles, underscoring the limitations of single-omic approaches. Upstream analysis identified protein arginine methyltransferase-1 (PRMT1) and integrins, particularly αVβ6, as potential master regulators and therapeutic targets. PRMT1 is implicated in ADMA-mediated nitric oxide inhibition and fibrosis, whereas integrin αVβ6 is associated with tubular injury and renal fibrogenesis. Notably, PRMT1 may activate STAT3, which in turn regulates integrin β6 expression, suggesting a novel PRMT1–STAT3–integrin αVβ6 axis in TACN pathogenesis. This study represents the first trans-omic approach to TACN, providing a foundation for mechanistic validation and therapeutic exploration of PRMT1 and integrins in both preclinical and clinical settings. Full article

Post-translational modifications (PTMs) of proteins in eukaryotic cells are essential for regulating proteome function and maintaining cellular homeostasis. Among these, the methylation modification of arginine has received much attention in recent years. The enzymatic process of arginine methylation is catalyzed by a family of approximately nine known protein arginine methyltransferases (PRMTs) in humans, which utilize S-adenosylmethionine (SAM) as the methyl group donor. PRMTs are involved in biological processes such as gene transcription, signal transduction, and DNA damage repair. Their role in normal cellular functions and pathological disease states is becoming increasingly clear with the advancement of research. This paper provides a review of the numerous roles of members of the PRMT family in normal cellular function and disease pathophysiology, with a focus on their association with the tumor immune microenvironment (TIME), and discusses their broad impact on various physiological processes and pathological conditions. Full article

Standard cancer chemotherapy is increasingly being supplemented with novel therapeutics to overcome known chemoresistance pathways. Resistance to treatment is common across various tumour types, driven by multiple mechanisms. One emerging contributor is protein methylation, a post-translational modification mediated by protein methyltransferases (PMTs), which regulate protein function by adding methyl groups, mainly on lysine and arginine residues. Dysregulation of protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) has been linked to cancer progression and drug resistance, making them attractive therapeutic targets. Consequently, several small-molecule PMT inhibitors have been developed, with some progressing to clinical trials. However, many candidates showing promise in preclinical studies fail to demonstrate efficacy or safety in later stages, limiting clinical success. This gap highlights the need to rethink current approaches to PMT inhibitor design. A deeper understanding of PMT mechanisms, catalytic domains, and their roles in chemoresistance is essential for creating more selective, potent, and clinically viable inhibitors. This review will summarise major chemoresistance pathways and PMTs implicated in cancer, then explore current and prospective PMT inhibitor classes. Building on mechanistic insights, we propose strategies to develop next-generation inhibitors with improved therapeutic potential against chemoresistant cancers. Full article

Type 2 Diabetes Mellitus (T2DM) is increasingly affecting individuals across various age groups due to inadequate insulin action and secretion. It has become the leading cause of mortality worldwide, with an estimated 9.3% of the global population currently affected. Recent epigenetic studies have shown that variations such as DNA methylation and histone modifications are implicated in the development of T2DM. However, epigenetically related conditions are known to be reversible, which could potentially pave the way for predicting and treating T2DM. This has led to the development of epigenetic modifier drugs, including histone deacetylase inhibitors (HDACi), histone acetyltransferase inhibitors (HATi), protein arginine methyltransferase inhibitors (PRMTi), DNA methyltransferase inhibitors (DNMTi), histone demethylating inhibitors (HDMi), and sirtuin-activating compounds (STAC). A major challenge with these epigenetic drugs is that only a few have been approved for treating metabolic diseases due to their potential to negatively impact off-target genes. The low specificity of these drugs can lead to side effects and increased toxicity, contributing to complex diseases such as cancer. Hence, gaining a comprehensive understanding of the epigenetic mechanisms underlying metabolic diseases can provide new insights and strategies for preventing, diagnosing, and treating metabolic disorders, such as T2DM. This review summarizes the epigenetic variations in T2DM, pharmaco-epigenetics, and the challenges surrounding epigenetics. This provides basic insight into the discovery of novel drug targets, which can lead to the development of epigenetic therapies for T2DM. Hence, the reversible nature of epigenetic variations retains hope for future novel strategies to combat T2DM. Full article

Epigenetic dysregulation is a hallmark of tumorigenesis, with arginine methylation—a post-translational modification—emerging as a key regulatory mechanism in cancer biology. This modification, catalyzed by protein arginine methyltransferases (PRMTs), influences critical cellular processes, including proliferation, differentiation, transcription, RNA splicing, DNA repair, and immune signaling. Among the PRMT family, PRMT5 has garnered significant attention due to its elevated expression across various solid tumors and hematological malignancies, and its strong association with poor clinical outcomes. Notably, PRMT5 exhibits a unique vulnerability in methyl-thio-adenosine phosphorylase (MTAP)-deficient cancers, making it an attractive therapeutic target. Recent advances have led to the development of several PRMT5 inhibitors with diverse binding modes, some of which have progressed into clinical trials for advanced cancers. This review provides a structural and mechanistic overview of PRMT5, summarizes current inhibition strategies, and discusses the challenges and future directions in targeting PRMT5 for cancer therapy. Full article

Human methyltransferase-like protein 16 (METTL16) installs N⁶-methyladenosine on U6 small nuclear RNA (snRNA) and other RNAs. Multiple X-ray crystal structures of METTL16 have been published; however, we do not yet fully understand the structure–function relationships of specific residues. We designed 38 mutants, including seven cancer-associated mutants, and used electrophoretic mobility shift assays and single-turnover kinetic assays to better understand the functional roles of specific domains and amino acid residues in binding to U6 snRNA, formation of the METTL16•U6 snRNA•S-adenosylmethionine (SAM) complex, and the rate of methylation. While point mutations in the methyltransferase domain mildly weaken the binding of METTL16 to U6 snRNA, the C-terminal vertebrate conserved regions (VCRs), particularly the arginine-rich region (R382 to R388), mediate cooperative binding and contribute more to RNA binding. All METTL16 K-loop mutants displayed tighter SAM binding, suggesting that the K-loop blocks SAM binding. In addition, residues E133 and F227 are critical for stabilizing SAM binding. Mutations in the ₁₈₄NPPF₁₈₇ catalytic core and R282A abolished methyltransferase activity. Two METTL16 somatic cancer-associated mutants (G110C and R241Dfs*2) displayed reduced methylation activity. This mutational analysis expands our understanding of how specific domains and residues contribute to substrate-binding activity and methylation of U6 snRNA catalyzed by METTL16. Full article

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with KRAS mutations present in nearly 45% of cases. Compared to KRAS wild-type (WT) CRC, KRAS-mutant CRC is associated with poorer prognosis and fewer effective treatment options. Protein Arginine Methyltransferase 5 (PRMT5), an epigenetic regulator involved in diverse cellular processes, is currently under investigation as a therapeutic target in multiple cancer types. Our previous work demonstrated that PRMT5 inhibition produces stronger therapeutic effects in KRAS-mutant CRC cells than in KRAS WT cells, suggesting potential crosstalk between PRMT5 and KRAS. In this study, we aimed to identify key downstream proteins that may mediate this interaction. Through a literature review, protein–protein interaction analysis (STRING database), gene expression analysis (GEPIA database), and correlation analysis (GEPIA database), we identified MYC, E2F1, and EIF4E as critical candidates. These proteins are shown to interact with both PRMT5 and KRAS in STRING, are overexpressed in CRC tumor samples, and show positive gene expression correlations with PRMT5 and KRAS in patient data. These findings are significant, as they provide new insights into the PRMT5–KRAS crosstalk and suggest potential targets for novel and combination therapies in KRAS-mutant CRC. Further research and biological experiments are needed to verify and outline the exact molecular processes behind MYC, E2F1, and EIF4E’s interactions with both PRMT5 and KRAS. Full article

Protein arginine methyltransferases (PRMTs) are a class of enzymes that mediate critical post-translational modifications through arginine methylation as epigenetic regulators. PRMTs have been shown to have a vast array of regulatory effects including in gene expression, signal transduction, and cellular proliferation. Dysregulation of PRMT activity has been seen in the progression of various cancers, including breast, lung, and colorectal cancer. Moreover, PRMT overexpression has been shown to correlate with poor patient prognosis. This review aims to explore the roles of the individual PRMTs in cancer and aims to highlight the latest and newest developments of PRMT inhibitors as emerging therapeutic strategies. Numerous preclinical and clinical studies have identified several novel compounds that effectively target PRMT activity and have shown significant therapeutic results. As such, this review aims to not only highlight the current research findings, but to also emphasize the significant need for future research on PRMTs as novel therapeutic targets in cancer. Full article

Colorectal cancer (CRC) is one of the most prevalent and deadly neoplasms globally; this fact puts emphasis on the need for accurate molecular biomarkers for early detection and accurate prognosis. Circular RNAs (circRNAs) have recently emerged as very promising cancer biomarkers. In this study, we thoroughly examined whether the expression levels of circular transcripts of the protein arginine methyltransferase 1 (PRMT1) gene can predict the prognosis of patients diagnosed with colorectal adenocarcinoma, the most frequent type of CRC. Hence, a highly sensitive quantitative PCR (qPCR) assay was developed and applied to quantify circ-PRMT1 expression in cDNAs from 210 primary colorectal adenocarcinoma tissue specimens and 86 paired normal colorectal mucosae. Extensive biostatistical analysis was then performed to assess the potential prognostic power of circ-PRMT1. Significant overexpression of this molecule was observed in colorectal adenocarcinoma tissue samples in contrast to their non-cancerous counterparts. Moreover, higher circ-PRMT1 expression was correlated with poorer disease-free survival (DFS) and worse overall survival (OS) in colorectal adenocarcinoma patients. Interestingly, multivariate Cox regression analysis revealed that the prognostic value of the expression of this circRNA does not depend on other established prognostic factors included in the prognostic model. Furthermore, the stratification of patients based on TNM staging revealed that higher circ-PRMT1 levels were significantly related to shorter DFS and OS intervals, particularly in patients with colorectal adenocarcinoma of TNM stage II or III. In summary, this original research study provides evidence that circ-PRMT1 overexpression represents a promising molecular biomarker of poor prognosis in colorectal adenocarcinoma, not depending on other established prognostic factors such as TNM staging. Full article