Epigenetic Regulation in Human Cancers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 37204

Special Issue Editor

1. Department of Biochemistry and Molecular Biology, Universitat de València, 46010 Valencia, Spain
2. Department of Oncology, Institute of Health Research INCLIVA, 46010 Valencia, Spain
Interests: alternative TSSs; alternative polyadenylation; mechanisms of RNA splicing; mRNA and protein isoforms; spliceosome; aberrant splicing; hRNPs; exon skipping; intron retention; spliceosomal diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The first draft of human genome sequences was published in an almost complete form in February 2001. Twenty years have now elapsed, and cancer research has taken incredible advantage of that prominent milestone. Nevertheless, there are several factors in addition to DNA sequencing that govern gene expression and, consequently, play essential roles in delineating the fate and behavior of cells. Methylation of DNA, post-translational modifications of histones, noncoding RNAs, and the chromatin structure itself are factors that decisively modulate gene function, giving additional—epigenetic—information to the genetic message. Within the framework of the growing interest in epigenetics, cancer represents one of the more relevant diseases. It was recognized early that “epimutations” play a distinct role in cancer onset and progression, and many papers have been published dealing with the epigenetic mechanisms controlling cancer. The utility of epigenetic modifications as biomarkers for cancer diagnosis and/or prognosis and to predict the efficiency of treatments has also drawn interest from many researchers. Moreover, as epimutations, in contrast to genetic mutations, are reversible, the development of epigenetic drugs is also an attractive field of research. In this way, epigenetics is opening a novel landscape to understand the causes of malignancy and to deal with therapeutic treatments, a task which cannot be approached solely with the knowledge of DNA sequence.

This Special Issue of Cancers aims to bring together basic and clinical oncologists to discuss the state of the art of research in epigenetics of cancer. Relevant papers describing either original investigation or expert reviews, which deal with basic mechanistic approaches, epigenomics of cancer cells, translational research, therapeutic applications, clinical trials with epigenetic drugs, etc., will be welcome.

Dr. Luis Franco
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • epigenomics
  • epigenetics of carcinogenesis
  • epigenetic drugs
  • microRNA
  • DNA methylation
  • histone modifications

Published Papers (11 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review, Other

19 pages, 1802 KiB  
Article
Epigenetic Alteration of the Cancer-Related Gene TGFBI in B Cells Infected with Epstein–Barr Virus and Exposed to Aflatoxin B1: Potential Role in Burkitt Lymphoma Development
by Francesca Manara, Antonin Jay, Grace Akinyi Odongo, Fabrice Mure, Mohamed Ali Maroui, Audrey Diederichs, Cecilia Sirand, Cyrille Cuenin, Massimo Granai, Lucia Mundo, Hector Hernandez-Vargas, Stefano Lazzi, Rita Khoueiry, Henri Gruffat, Zdenko Herceg and Rosita Accardi
Cancers 2022, 14(5), 1284; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051284 - 02 Mar 2022
Cited by 2 | Viewed by 3456
Abstract
Burkitt lymphoma (BL) is a malignant B cell neoplasm that accounts for almost half of pediatric cancers in sub-Saharan African countries. Although the BL endemic prevalence is attributable to the combination of Epstein–Barr virus (EBV) infection with malaria and environmental carcinogens exposure, such [...] Read more.
Burkitt lymphoma (BL) is a malignant B cell neoplasm that accounts for almost half of pediatric cancers in sub-Saharan African countries. Although the BL endemic prevalence is attributable to the combination of Epstein–Barr virus (EBV) infection with malaria and environmental carcinogens exposure, such as the food contaminant aflatoxin B1 (AFB1), the molecular determinants underlying the pathogenesis are not fully understood. Consistent with the role of epigenetic mechanisms at the interface between the genome and environment, AFB1 and EBV impact the methylome of respectively leukocytes and B cells specifically. Here, we conducted a thorough investigation of common epigenomic changes following EBV or AFB1 exposure in B cells. Genome-wide DNA methylation profiling identified an EBV–AFB1 common signature within the TGFBI locus, which encodes for a putative tumor suppressor often altered in cancer. Subsequent mechanistic analyses confirmed a DNA-methylation-dependent transcriptional silencing of TGFBI involving the recruitment of DNMT1 methyltransferase that is associated with an activation of the NF-κB pathway. Our results reveal a potential common mechanism of B cell transformation shared by the main risk factors of endemic BL (EBV and AFB1), suggesting a key determinant of disease that could allow the development of more efficient targeted therapeutic strategies. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

27 pages, 9396 KiB  
Article
Locus-Specific DNA Methylation Editing in Melanoma Cell Lines Using a CRISPR-Based System
by Jim Smith, Rakesh Banerjee, Reema Waly, Arthur Urbano, Gregory Gimenez, Robert Day, Michael R. Eccles, Robert J. Weeks and Aniruddha Chatterjee
Cancers 2021, 13(21), 5433; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215433 - 29 Oct 2021
Cited by 8 | Viewed by 3663
Abstract
DNA methylation is a key epigenetic modification implicated in the pathogenesis of numerous human diseases, including cancer development and metastasis. Gene promoter methylation changes are widely associated with transcriptional deregulation and disease progression. The advent of CRISPR-based technologies has provided a powerful toolkit [...] Read more.
DNA methylation is a key epigenetic modification implicated in the pathogenesis of numerous human diseases, including cancer development and metastasis. Gene promoter methylation changes are widely associated with transcriptional deregulation and disease progression. The advent of CRISPR-based technologies has provided a powerful toolkit for locus-specific manipulation of the epigenome. Here, we describe a comprehensive global workflow for the design and application of a dCas9-SunTag-based tool for editing the DNA methylation locus in human melanoma cells alongside protocols for downstream techniques used to evaluate subsequent methylation and gene expression changes in methylation-edited cells. Using transient system delivery, we demonstrate both highly efficacious methylation and demethylation of the EBF3 promoter, which is a putative epigenetic driver of melanoma metastasis, achieving up to a 304.00% gain of methylation and 99.99% relative demethylation, respectively. Furthermore, we employ a novel, targeted screening approach to confirm the minimal off-target activity and high on-target specificity of our designed guide RNA within our target locus. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

14 pages, 1169 KiB  
Article
Global Methylome Scores Correlate with Histological Subtypes of Colorectal Carcinoma and Show Different Associations with Common Clinical and Molecular Features
by María del Carmen Turpín-Sevilla, Fernando Pérez-Sanz, José García-Solano, Patricia Sebastián-León, Javier Trujillo-Santos, Pablo Carbonell, Eduardo Estrada, Anne Tuomisto, Irene Herruzo, Lochlan J. Fennell, Markus J. Mäkinen, Edith Rodríguez-Braun, Vicki L. J. Whitehall, Ana Conesa and Pablo Conesa-Zamora
Cancers 2021, 13(20), 5165; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205165 - 14 Oct 2021
Viewed by 2451
Abstract
Background. The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina’s 450 k Infinium [...] Read more.
Background. The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina’s 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI-H), and, additionally, 35 normal adjacent mucosae. Scores reflecting the overall methylation at 250 bp, 1 kb and 2 kb from the transcription starting site (TSS) were studied. Results. SAC has an intermediate methylation pattern between CC and hmMSI-H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250 bp and 1 Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores). Conclusion. These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Graphical abstract

16 pages, 3911 KiB  
Article
Neuronal Differentiation-Related Epigenetic Regulator ZRF1 Has Independent Prognostic Value in Neuroblastoma but Is Functionally Dispensable In Vitro
by Carlos Jiménez, Roberta Antonelli, Marc Masanas, Aroa Soriano, Laura Devis-Jauregui, Jessica Camacho, Ainara Magdaleno, Gabriela Guillén, Raquel Hladun, Luz Jubierre, Josep Roma, David Llobet-Navas, Josep Sánchez de Toledo, Lucas Moreno, Soledad Gallego and Miguel F. Segura
Cancers 2021, 13(19), 4845; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194845 - 28 Sep 2021
Viewed by 1779
Abstract
Neuroblastoma is a pediatric tumor of the peripheral nervous system that accounts for up to ~15% of all cancer-related deaths in children. Recently, it has become evident that epigenetic deregulation is a relevant event in pediatric tumors such as high-risk neuroblastomas, and a [...] Read more.
Neuroblastoma is a pediatric tumor of the peripheral nervous system that accounts for up to ~15% of all cancer-related deaths in children. Recently, it has become evident that epigenetic deregulation is a relevant event in pediatric tumors such as high-risk neuroblastomas, and a determinant for processes, such as cell differentiation blockade and sustained proliferation, which promote tumor progression and resistance to current therapies. Thus, a better understanding of epigenetic factors implicated in the aggressive behavior of neuroblastoma cells is crucial for the development of better treatments. In this study, we characterized the role of ZRF1, an epigenetic activator recruited to genes involved in the maintenance of the identity of neural progenitors. We combined analysis of patient sample expression datasets with loss- and gain-of-function studies on neuroblastoma cell lines. Functional analyses revealed that ZRF1 is functionally dispensable for those cellular functions related to cell differentiation, proliferation, migration, and invasion, and does not affect the cellular response to chemotherapeutic agents. However, we found that high levels of ZRF1 mRNA expression are associated to shorter overall survival of neuroblastoma patients, even when those patients with the most common molecular alterations used as prognostic factors are removed from the analyses, thereby suggesting that ZRF1 expression could be used as an independent prognostic factor in neuroblastoma. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

13 pages, 2297 KiB  
Article
Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
by Victor M. Matias-Barrios, Mariia Radaeva, Chia-Hao Ho, Joseph Lee, Hans Adomat, Nada Lallous, Artem Cherkasov and Xuesen Dong
Cancers 2021, 13(15), 3675; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153675 - 22 Jul 2021
Cited by 8 | Viewed by 2626
Abstract
Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different [...] Read more.
Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

Review

Jump to: Research, Other

22 pages, 1475 KiB  
Review
Epigenetics of Dendritic Cells in Tumor Immunology
by Gerard Godoy-Tena and Esteban Ballestar
Cancers 2022, 14(5), 1179; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051179 - 24 Feb 2022
Cited by 11 | Viewed by 3679
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells with the distinctive property of inducing the priming and differentiation of naïve CD4+ and CD8+ T cells into helper and cytotoxic effector T cells to develop efficient tumor-immune responses. DCs display pathogenic and tumorigenic antigens on [...] Read more.
Dendritic cells (DCs) are professional antigen-presenting cells with the distinctive property of inducing the priming and differentiation of naïve CD4+ and CD8+ T cells into helper and cytotoxic effector T cells to develop efficient tumor-immune responses. DCs display pathogenic and tumorigenic antigens on their surface through major histocompatibility complexes to directly influence the differentiation of T cells. Cells in the tumor microenvironment (TME), including cancer cells and other immune-infiltrated cells, can lead DCs to acquire an immune-tolerogenic phenotype that facilitates tumor progression. Epigenetic alterations contribute to cancer development, not only by directly affecting cancer cells, but also by their fundamental role in the differentiation of DCs that acquire a tolerogenic phenotype that, in turn, suppresses T cell-mediated responses. In this review, we focus on the epigenetic regulation of DCs that have infiltrated the TME and discuss how knowledge of the epigenetic control of DCs can be used to improve DC-based vaccines for cancer immunotherapy. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

23 pages, 1108 KiB  
Review
DNA Methylation in Lung Cancer: Mechanisms and Associations with Histological Subtypes, Molecular Alterations, and Major Epidemiological Factors
by Phuc H. Hoang and Maria Teresa Landi
Cancers 2022, 14(4), 961; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040961 - 15 Feb 2022
Cited by 23 | Viewed by 4276
Abstract
Lung cancer is the major leading cause of cancer-related mortality worldwide. Multiple epigenetic factors—in particular, DNA methylation—have been associated with the development of lung cancer. In this review, we summarize the current knowledge on DNA methylation alterations in lung tumorigenesis, as well as [...] Read more.
Lung cancer is the major leading cause of cancer-related mortality worldwide. Multiple epigenetic factors—in particular, DNA methylation—have been associated with the development of lung cancer. In this review, we summarize the current knowledge on DNA methylation alterations in lung tumorigenesis, as well as their associations with different histological subtypes, common cancer driver gene mutations (e.g., KRAS, EGFR, and TP53), and major epidemiological risk factors (e.g., sex, smoking status, race/ethnicity). Understanding the mechanisms of DNA methylation regulation and their associations with various risk factors can provide further insights into carcinogenesis, and create future avenues for prevention and personalized treatments. In addition, we also highlight outstanding questions regarding DNA methylation in lung cancer to be elucidated in future studies Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

18 pages, 1439 KiB  
Review
Dissecting TET2 Regulatory Networks in Blood Differentiation and Cancer
by Aleksey Lazarenkov and José Luis Sardina
Cancers 2022, 14(3), 830; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030830 - 06 Feb 2022
Cited by 8 | Viewed by 4062
Abstract
Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation [...] Read more.
Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation can be either passive or active when initiated by TET dioxygenases. During active demethylation, transcription factors (TFs) recruit TET enzymes (TET1, 2, and 3) to specific gene regulatory regions to first catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and subsequently to higher oxidized cytosine derivatives. Only TET2 is frequently mutated in the hematopoietic system from the three TET family members. These mutations initially lead to the hematopoietic stem cells (HSCs) compartment expansion, eventually evolving to give rise to a wide range of blood malignancies. This review focuses on recent advances in characterizing the main TET2-mediated molecular mechanisms that activate aberrant transcriptional programs in blood cancer onset and development. In addition, we discuss some of the key outstanding questions in the field. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

23 pages, 1240 KiB  
Review
Alternative Splicing, Epigenetic Modifications and Cancer: A Dangerous Triangle, or a Hopeful One?
by Francisco Gimeno-Valiente, Gerardo López-Rodas, Josefa Castillo and Luis Franco
Cancers 2022, 14(3), 560; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030560 - 22 Jan 2022
Cited by 14 | Viewed by 4269
Abstract
The alteration of epigenetic modifications often causes cancer onset and development. In a similar way, aberrant alternative splicing may result in oncogenic products. These issues have often been individually reviewed, but there is a growing body of evidence for the interconnection of both [...] Read more.
The alteration of epigenetic modifications often causes cancer onset and development. In a similar way, aberrant alternative splicing may result in oncogenic products. These issues have often been individually reviewed, but there is a growing body of evidence for the interconnection of both causes of cancer. Actually, aberrant splicing may result from abnormal epigenetic signalization and epigenetic factors may be altered by alternative splicing. In this way, the interrelation between epigenetic marks and alternative splicing form the base of a triangle, while cancer may be placed at the vertex. The present review centers on the interconnections at the triangle base, i.e., between alternative splicing and epigenetic modifications, which may result in neoplastic transformations. The effects of different epigenetic factors, including DNA and histone modifications, the binding of non-coding RNAs and the alterations of chromatin organization on alternative splicing resulting in cancer are first considered. Other less-frequently considered questions, such as the epigenetic regulation of the splicing machinery, the aberrant splicing of epigenetic writers, readers and erasers, etc., are next reviewed in their connection with cancer. The knowledge of the above-mentioned relationships has allowed increasing the collection of biomarkers potentially useful as cancer diagnostic and/or prognostic tools. Finally, taking into account on one hand that epigenetic changes are reversible, and some epigenetic drugs already exist and, on the other hand, that drugs intended for reversing aberrations in alternative splicing, therapeutic possibilities for breaking the mentioned cancer-related triangle are discussed. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

14 pages, 575 KiB  
Review
Experimental and Bioinformatic Approaches to Studying DNA Methylation in Cancer
by Angelika Merkel and Manel Esteller
Cancers 2022, 14(2), 349; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020349 - 11 Jan 2022
Cited by 6 | Viewed by 3812
Abstract
DNA methylation is an essential epigenetic mark. Alterations of normal DNA methylation are a defining feature of cancer. Here, we review experimental and bioinformatic approaches to showcase the breadth and depth of information that this epigenetic mark provides for cancer research. First, we [...] Read more.
DNA methylation is an essential epigenetic mark. Alterations of normal DNA methylation are a defining feature of cancer. Here, we review experimental and bioinformatic approaches to showcase the breadth and depth of information that this epigenetic mark provides for cancer research. First, we describe classical approaches for interrogating bulk DNA from cell populations as well as more recently developed approaches for single cells and multi-Omics. Second, we focus on the computational analysis from primary data processing to the identification of unique methylation signatures. Additionally, we discuss challenges such as sparse data and cellular heterogeneity. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Show Figures

Figure 1

Other

Jump to: Research, Review

16 pages, 262 KiB  
Systematic Review
Epigenetic Modifiers as Novel Therapeutic Targets and a Systematic Review of Clinical Studies Investigating Epigenetic Inhibitors in Head and Neck Cancer
by Kyunghee Burkitt and Vassiliki Saloura
Cancers 2021, 13(20), 5241; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205241 - 19 Oct 2021
Cited by 8 | Viewed by 1845
Abstract
The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of [...] Read more.
The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and discusses results of clinical trials evaluating epigenetic interventions in past and ongoing clinical trials as monotherapy or combination therapy with either chemotherapy, radiotherapy or immunotherapy. Understanding the function of epigenetic modifiers in both preclinical and clinical settings will provide insight into a more rational design of clinical trials using epigenetic interventions and the patient subgroups that may benefit from such interventions. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)
Back to TopTop