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Epigenetic Regulation and Cancers

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 20577

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Special Issue Editors

Dr. Eleonora A. Braga

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Guest Editor

Institute of General Pathology and Pathophysiology RAMS, Moscow, Russia
Interests: genomics; gene exspression regulation; DNA methylation; miRNA; lncRNA

Dr. Irina Pronina

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Guest Editor

Institute of General Pathology and Physiopathology, Moscow, Russia
Interests: microRNAs; long non-coding RNAs; circulating microRNAs; epigenomics; transcriptomics; gene expression regulation

Special Issue Information

Dear Colleagues,

As it turned out over the past 2 decades, supragenomic or epigenetic regulation, which does not affect the DNA nucleotide sequence, plays a crucial role in cancer. One of the first epigenetic mechanisms was attributed to DNA methylation and histone modifications, which deregulate genes expression at the genomic level and play an important role in the pathogenesis of cancers of different localizations. After deciphering the human genome, it turned out that protein-coding genes occupy a tiny fraction of the human genome (~2%), and more than 70% of the transcripts are non-protein-coding RNAs (ncRNAs). Most noncoding transcripts exhibit nuclear localization, and many ncRNAs were shown to play a role in the regulation of gene expression and chromatin remodeling. Revolution in cancer biology was the discovery of microRNAs (miRNAs), which bind to mRNAs and inhibit the expression of protein-coding genes at the post-transcriptional level. Many miRNAs were shown to be involved in signaling pathways and significant biological processes in cancer. The next most interesting discovery was the identification of lncRNAs and then circRNAs and their participation in multilayer regulation of genes through the lncRNA(circRNA)/miRNA/mRNA axes by the mechanism of competing endogenous RNA (ceRNA). Alternative regulatory mechanisms based on the interaction of lncRNAs or circRNAs with mRNAs, proteins, DNA, etc. without miRNA mediation were also identified in cancers of various origins. In the last decade, the regulatory role of RNA methylation was discovered and extensively investigated in the carcinogenesis.

Nowadays, detailed study of genome-wide RNA-chromatin interactions became possible. Thus, the epigenetic regulation in cancer is carried out at multiple intersecting levels, forming complex regulatory networks. Epigenetic regulatory mechanisms have an effect on all processes in cancer progression and metastasis, as well as on survival and response to treatment of patients. Our special issue "Epigenetic Regulation and Cancers" invites original articles and comprehensive reviews covering any aspects of epigenetic regulation in cancer to highlight their functional and clinical significance.

Dr. Eleonora A. Braga
Dr. Irina Pronina
Guest Editors

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Keywords

cancer
epigenetic regulation
DNA methylation
RNA methylation
transcriptomics
mRNA
miRNA
ncRNA
ceRNA mechanism
chromatin remodeling

Published Papers (10 papers)

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Research

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28 pages, 8495 KiB

Open AccessArticle

Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors

by Angelika V. Timofeeva, Ivan S. Fedorov, Aleksandra V. Asaturova, Maya V. Sannikova, Anna V. Tregubova, Oleg A. Mayboroda, Grigory N. Khabas, Vladimir E. Frankevich and Gennady T. Sukhikh

Int. J. Mol. Sci. 2023, 24(15), 12214; https://doi.org/10.3390/ijms241512214 - 30 Jul 2023

Cited by 3 | Viewed by 1447

Abstract

The expression level of the progesterone receptor (PGR) plays a crucial role in determining the biological characteristics of serous ovarian carcinoma. Low PGR expression is associated with chemoresistance and a poorer outcome. In this study, our objective was to explore the relationship between tumor progesterone receptor levels and RNA profiles (miRNAs, piwiRNAs, and mRNAs) to understand their biological characteristics and behavior. To achieve this, we employed next-generation sequencing of small non-coding RNAs, quantitative RT-PCR, and immunohistochemistry to analyze both FFPE and frozen tumor samples, as well as blood plasma from patients with benign cystadenoma (BSC), serous borderline tumor (SBT), low-grade serous ovarian carcinoma (LGSOC), and high-grade serous ovarian carcinoma (HGSOC). Our findings revealed significant upregulation of MMP7 and MUC16, along with downregulation of PGR, in LGSOC and HGSOC compared to BSC. We observed significant correlations of PGR expression levels in tumor tissue with the contents of miR-199a-5p, miR-214-3p, miR-424-3p, miR-424-5p, and miR-125b-5p, which potentially target MUC16, MMP7, and MMP9, as well as with the tissue content of miR-16-5p, miR-17-5p, miR-20a-5p, and miR-93-5p, which are associated with the epithelial–mesenchymal transition (EMT) of cells. The levels of EMT-associated miRNAs were significantly correlated with the content of hsa_piR_022437, hsa_piR_009295, hsa_piR_020813, hsa_piR_004307, and hsa_piR_019914 in tumor tissues. We developed two optimal logistic regression models using the quantitation of hsa_piR_020813, miR-16-5p, and hsa_piR_022437 or hsa_piR_004307, hsa_piR_019914, and miR-93-5p in the tumor tissue, which exhibited a significant ability to diagnose the PGR-negative tumor phenotype with 93% sensitivity. Of particular interest, the blood plasma levels of miR-16-5p and hsa_piR_022437 could be used to diagnose the PGR-negative tumor phenotype with 86% sensitivity even before surgery and chemotherapy. This knowledge can help in choosing the most effective treatment strategy for this aggressive type of ovarian cancer, such as neoadjuvant chemotherapy followed by cytoreduction in combination with hyperthermic intraperitoneal chemotherapy and targeted therapy, thus enhancing the treatment’s effectiveness and the patient’s longevity. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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15 pages, 2209 KiB

Open AccessArticle

The SDHD:p.H102R Variant Is Frequent in Russian Patients with Head and Neck Paragangliomas and Associated with Loss of 11p15.5 Region and Hypermethylation of H19-DMR

by Anastasiya Snezhkina, Maria Fedorova, Anastasiya Kobelyatskaya, Daria Markova, Margarita Lantsova, Anna Ikonnikova, Marina Emelyanova, Dmitry Kalinin, Elena Pudova, Nataliya Melnikova, Alexey Dmitriev, George Krasnov, Vladislav Pavlov and Anna Kudryavtseva

Int. J. Mol. Sci. 2023, 24(1), 628; https://doi.org/10.3390/ijms24010628 - 30 Dec 2022

Cited by 3 | Viewed by 1626

Abstract

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms derived from the parasympathetic paraganglia of the head and neck. At least 30% of HNPGLs are linked to germline mutations, predominantly in SDHx genes. In this study, we analyzed an extended cohort of Russian patients with HNPGLs using whole-exome sequencing and found a highly frequent missense variant p.H102R in the SDHD gene. We determined this variant in 34% of the SDHD mutation carriers. This variant was associated with somatic loss of the gene wild-type allele. Data from the B allele frequency method and microsatellite and microdeletion analysis indicated evident LOH at the 11p15.5 region and potential loss of the whole of chromosome 11. We found hypermethylation of H19-DMR in all tumors, whereas differential methylation of KvDMR was mostly retained. These findings do not support the paternal transmission of SDHD:p.H102R but are in agreement with the Hensen model. Using targeted sequencing, we also studied the variant frequency in a control cohort; we found SDHD:p.H102R in 1.9% of cases, allowing us to classify this variant as pathogenic. The immunohistochemistry of SDHB showed that the SDHD:p.H102R mutation, even in combination with wild-type allele loss, does not always lead to SDH deficiency. The obtained results demonstrate the frequent variant associated with HNPGLs in a Russian population and support its pathogenicity. Our findings help with understanding the mechanism of tumorigenesis and are also important for the development of cost-effective genetic screening programs. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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Review

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34 pages, 764 KiB

Open AccessReview

Circulating Tumor DNA Is a Variant of Liquid Biopsy with Predictive and Prognostic Clinical Value in Breast Cancer Patients

by Tatiana M. Zavarykina, Polina K. Lomskova, Irina V. Pronina, Svetlana V. Khokhlova, Marina B. Stenina and Gennady T. Sukhikh

Int. J. Mol. Sci. 2023, 24(23), 17073; https://doi.org/10.3390/ijms242317073 - 2 Dec 2023

Cited by 2 | Viewed by 1672

Abstract

This paper introduces the reader to the field of liquid biopsies and cell-free nucleic acids, focusing on circulating tumor DNA (ctDNA) in breast cancer (BC). BC is the most common type of cancer in women, and progress with regard to treatment has been made in recent years. Despite this, there remain a number of unresolved issues in the treatment of BC; in particular, early detection and diagnosis, reliable markers of response to treatment and for the prediction of recurrence and metastasis, especially for unfavorable subtypes, are needed. It is also important to identify biomarkers for the assessment of drug resistance and for disease monitoring. Our work is devoted to ctDNA, which may be such a marker. Here, we describe its main characteristics and potential applications in clinical oncology. This review considers the results of studies devoted to the analysis of the prognostic and predictive roles of various methods for the determination of ctDNA in BC patients. Currently known epigenetic changes in ctDNA with clinical significance are reviewed. The possibility of using ctDNA as a predictive and prognostic marker for monitoring BC and predicting the recurrence and metastasis of cancer is also discussed, which may become an important part of a precision approach to the treatment of BC. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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34 pages, 18596 KiB

Open AccessReview

Various LncRNA Mechanisms in Gene Regulation Involving miRNAs or RNA-Binding Proteins in Non-Small-Cell Lung Cancer: Main Signaling Pathways and Networks

by Eleonora A. Braga, Marina V. Fridman, Alexey M. Burdennyy, Vitaly I. Loginov, Alexey A. Dmitriev, Irina V. Pronina and Sergey G. Morozov

Int. J. Mol. Sci. 2023, 24(17), 13617; https://doi.org/10.3390/ijms241713617 - 3 Sep 2023

Cited by 4 | Viewed by 1854

Abstract

Long non-coding RNAs (lncRNAs) are crucial players in the pathogenesis of non-small-cell lung cancer (NSCLC). A competing binding of lncRNAs and mRNAs with microRNAs (miRNAs) is one of the most common mechanisms of gene regulation by lncRNAs in NSCLC, which has been extensively researched in the last two decades. However, alternative mechanisms that do not depend on miRNAs have also been reported. Among them, the most intriguing mechanism is mediated by RNA-binding proteins (RBPs) such as IGF2BP1/2/3, YTHDF1, HuR, and FBL, which increase the stability of target mRNAs. IGF2BP2 and YTHDF1 may also be involved in m⁶A modification of lncRNAs or target mRNAs. Some lncRNAs, such as DLGAP1-AS2, MALAT1, MNX1-AS1, and SNHG12, are involved in several mechanisms depending on the target: lncRNA/miRNA/mRNA interactome and through RBP. The target protein sets selected here were then analyzed using the DAVID database to identify the pathways overrepresented by KEGG, Wikipathways, and the Reactome pathway. Using the STRING website, we assessed interactions between the target proteins and built networks. Our analysis revealed that the JAK-STAT and Hippo signaling pathways, cytokine pathways, the VEGFA-VEGFR2 pathway, mechanisms of cell cycle regulation, and neovascularization are the most relevant to the effect of lncRNA on NSCLC. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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23 pages, 1462 KiB

Open AccessReview

MiRNA-146a—A Key Player in Immunity and Diseases

by Irina Gilyazova, Dilara Asadullina, Evelina Kagirova, Ruhi Sikka, Artur Mustafin, Elizaveta Ivanova, Ksenia Bakhtiyarova, Gulshat Gilyazova, Saurabh Gupta, Elza Khusnutdinova, Himanshu Gupta and Valentin Pavlov

Int. J. Mol. Sci. 2023, 24(16), 12767; https://doi.org/10.3390/ijms241612767 - 14 Aug 2023

Cited by 3 | Viewed by 1902

Abstract

miRNA-146a, a single-stranded, non-coding RNA molecule, has emerged as a valuable diagnostic and prognostic biomarker for numerous pathological conditions. Its primary function lies in regulating inflammatory processes, haemopoiesis, allergic responses, and other key aspects of the innate immune system. Several studies have indicated that polymorphisms in miRNA-146a can influence the pathogenesis of various human diseases, including autoimmune disorders and cancer. One of the key mechanisms by which miRNA-146a exerts its effects is by controlling the expression of certain proteins involved in critical pathways. It can modulate the activity of interleukin-1 receptor-associated kinase, IRAK1, IRAK2 adaptor proteins, and tumour necrosis factor (TNF) targeting protein receptor 6, which is a regulator of the TNF signalling pathway. In addition, miRNA-146a affects gene expression through multiple signalling pathways, such as TNF, NF-κB and MEK-1/2, and JNK-1/2. Studies have been carried out to determine the effect of miRNA-146a on cancer pathogenesis, revealing its involvement in the synthesis of stem cells, which contributes to tumourigenesis. In this review, we focus on recent discoveries that highlight the significant role played by miRNA-146a in regulating various defence mechanisms and oncogenesis. The aim of this review article is to systematically examine miRNA-146a’s impact on the control of signalling pathways involved in oncopathology, immune system development, and the corresponding response to therapy. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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20 pages, 1601 KiB

Open AccessReview

SWI/SNF Complex Alterations in Tumors with Rhabdoid Features: Novel Therapeutic Approaches and Opportunities for Adoptive Cell Therapy

by Juan José Soto-Castillo, Lucía Llavata-Marti, Roser Fort-Culillas, Pablo Andreu-Cobo, Rafael Moreno, Carles Codony, Xavier García del Muro, Ramon Alemany, Josep M. Piulats and Juan Martin-Liberal

Int. J. Mol. Sci. 2023, 24(13), 11143; https://doi.org/10.3390/ijms241311143 - 6 Jul 2023

Cited by 2 | Viewed by 1422

Abstract

The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is one of the most remarkably altered epigenetic regulators in cancer. Pathogenic mutations in genes encoding SWI/SNF-related proteins have been recently described in many solid tumors, including rare and aggressive malignancies with rhabdoid features with no standard therapies in advanced or metastatic settings. In recent years, clinical trials with targeted drugs aimed at restoring its function have shown discouraging results. However, preclinical data have found an association between these epigenetic alterations and response to immune therapy. Thus, the rationale for immunotherapy strategies in SWI/SNF complex alteration-related tumors is strong. Here, we review the SWI/SNF complex and how its dysfunction drives the oncogenesis of rhabdoid tumors and the proposed strategies to revert this alteration and promising novel therapeutic approaches, including immune checkpoint inhibition and adoptive cell therapy. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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20 pages, 895 KiB

Open AccessReview

Exploring the Potential Role of Circulating microRNAs as Biomarkers for Predicting Clinical Response to Neoadjuvant Therapy in Breast Cancer

by Luis M. Ruiz-Manriquez, Cynthia Villarreal-Garza, Javier A. Benavides-Aguilar, Andrea Torres-Copado, José Isidoro-Sánchez, Carolina Estrada-Meza, María Goretti Arvizu-Espinosa, Sujay Paul and Raquel Cuevas-Diaz Duran

Int. J. Mol. Sci. 2023, 24(12), 9984; https://doi.org/10.3390/ijms24129984 - 10 Jun 2023

Cited by 4 | Viewed by 1433

Abstract

Breast cancer (BC) is a leading cause of cancer-related deaths among women worldwide. Neoadjuvant therapy (NAT) is increasingly being used to reduce tumor burden prior to surgical resection. However, current techniques for assessing tumor response have significant limitations. Additionally, drug resistance is commonly observed, raising a need to identify biomarkers that can predict treatment sensitivity and survival outcomes. Circulating microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have been shown to play a significant role in cancer progression as tumor inducers or suppressors. The expression of circulating miRNAs has been found to be significantly altered in breast cancer patients. Moreover, recent studies have suggested that circulating miRNAs can serve as non-invasive biomarkers for predicting response to NAT. Therefore, this review provides a brief overview of recent studies that have demonstrated the potential of circulating miRNAs as biomarkers for predicting the clinical response to NAT in BC patients. The findings of this review will strengthen future research on developing miRNA-based biomarkers and their translation into medical practice, which could significantly improve the clinical management of BC patients undergoing NAT. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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27 pages, 473 KiB

Open AccessReview

Epigenetic and Immunological Features of Bladder Cancer

by Irina Gilyazova, Kadriia Enikeeva, Guzel Rafikova, Evelina Kagirova, Yuliya Sharifyanova, Dilara Asadullina and Valentin Pavlov

Int. J. Mol. Sci. 2023, 24(12), 9854; https://doi.org/10.3390/ijms24129854 - 7 Jun 2023

Cited by 1 | Viewed by 1838

Abstract

Bladder cancer (BLCA) is one of the most common types of malignant tumors of the urogenital system in adults. Globally, the incidence of BLCA is more than 500,000 new cases worldwide annually, and every year, the number of registered cases of BLCA increases noticeably. Currently, the diagnosis of BLCA is based on cystoscopy and cytological examination of urine and additional laboratory and instrumental studies. However, cystoscopy is an invasive study, and voided urine cytology has a low level of sensitivity, so there is a clear need to develop more reliable markers and test systems for detecting the disease with high sensitivity and specificity. Human body fluids (urine, serum, and plasma) are known to contain significant amounts of tumorigenic nucleic acids, circulating immune cells and proinflammatory mediators that can serve as noninvasive biomarkers, particularly useful for early cancer detection, follow-up of patients, and personalization of their treatment. The review describes the most significant advances in epigenetics of BLCA. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

19 pages, 1015 KiB

Open AccessReview

Histone Modifications Represent a Key Epigenetic Feature of Epithelial-to-Mesenchyme Transition in Pancreatic Cancer

by Ying Xu and Qing Zhu

Int. J. Mol. Sci. 2023, 24(5), 4820; https://doi.org/10.3390/ijms24054820 - 2 Mar 2023

Cited by 4 | Viewed by 1959

Abstract

Pancreatic cancer is one of the most lethal malignant diseases due to its high invasiveness, early metastatic properties, rapid disease progression, and typically late diagnosis. Notably, the capacity for pancreatic cancer cells to undergo epithelial–mesenchymal transition (EMT) is key to their tumorigenic and metastatic potential, and is a feature that can explain the therapeutic resistance of such cancers to treatment. Epigenetic modifications are a central molecular feature of EMT, for which histone modifications are most prevalent. The modification of histones is a dynamic process typically carried out by pairs of reverse catalytic enzymes, and the functions of these enzymes are increasingly relevant to our improved understanding of cancer. In this review, we discuss the mechanisms through which histone-modifying enzymes regulate EMT in pancreatic cancer. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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12 pages, 784 KiB

Open AccessReview

Cell-Free DNA Fragmentomics: The Novel Promising Biomarker

by Ting Qi, Min Pan, Huajuan Shi, Liangying Wang, Yunfei Bai and Qinyu Ge

Int. J. Mol. Sci. 2023, 24(2), 1503; https://doi.org/10.3390/ijms24021503 - 12 Jan 2023

Cited by 9 | Viewed by 4547

Abstract

Cell-free DNA molecules are released into the plasma via apoptotic or necrotic events and active release mechanisms, which carry the genetic and epigenetic information of its origin tissues. However, cfDNA is the mixture of various cell fragments, and the efficient enrichment of cfDNA fragments with diagnostic value remains a great challenge for application in the clinical setting. Evidence from recent years shows that cfDNA fragmentomics’ characteristics differ in normal and diseased individuals without the need to distinguish the source of the cfDNA fragments, which makes it a promising novel biomarker. Moreover, cfDNA fragmentomics can identify tissue origins by inferring epigenetic information. Thus, further insights into the fragmentomics of plasma cfDNA shed light on the origin and fragmentation mechanisms of cfDNA during physiological and pathological processes in diseases and enhance our ability to take the advantage of plasma cfDNA as a molecular diagnostic tool. In this review, we focus on the cfDNA fragment characteristics and its potential application, such as fragment length, end motifs, jagged ends, preferred end coordinates, as well as nucleosome footprints, open chromatin region, and gene expression inferred by the cfDNA fragmentation pattern across the genome. Furthermore, we summarize the methods for deducing the tissue of origin by cfDNA fragmentomics. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Cancers)

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