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The Epigenetic Landscape in Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 June 2024 | Viewed by 5922

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Special Issue Editors

Dr. Alessandra Gambacurta

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Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy
Interests: cancer biology; gene expression; stem cells; veterinary medicine; tissue engineering; epigenetic reprogramming; epigenetic therapy; histone code; histone modification; cancer cell metabolism

Dr. Maria Valeria Catani

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Guest Editor

Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy
Interests: platelets; oxidative stress; cancer; vitamin C; blood coagulation; inflammation; apoptosis; bioactive lipids; redox-sensitive transcription factors; microRNAs
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Dr. Valeria Gasperi

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Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy
Interests: cancer biology; microRNAs; epigenetics; apoptosis and differentiation; platelets; inflammation; cell-to-cell crosstalk; bioactive lipids
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Special Issue Information

Dear Colleagues,

Epigenetics affect gene expression through molecular mechanisms including DNA methylation, histone modifications (methylation, acetylation, ubiquitylation and phosphorylation), without modifying the DNA sequence, but affecting chromatin structure, RNA-associated gene silencing and chromosome inactivation.

The concept of an “epigenetic landscape” has been formulated in 1942 by Conrad Waddington, who described the process of cellular decision-making during development occurring when cells assume different, functionally important and heritable fates, without associated genetic or environmental differences. This innovative theory provided the framework for modern epigenetics, and today, evidence has highlighted the associations between epigenetic modifications and human diseases. Remarkably, cancer is now defined as both a genetic and an epigenetic disease, and epigenetic alterations play a significant role in cancer initiation, progression and metastasis.

This Special Issue will provide an up-to-date description of the more intriguing aspects of epigenetics in human cancer. Both original research articles and comprehensive reviews are welcomed.

Dr. Alessandra Gambacurta
Dr. Maria Valeria Catani
Dr. Valeria Gasperi
Guest Editors

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Keywords

cancer
cancer therapy
chromatin remodelling
chromosome inactivation
epigenetic reprogramming
gene silencing
histone modifications
metastasis
methylation
microRNAs

Published Papers (4 papers)

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Research

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17 pages, 2476 KiB

Open AccessArticle

Genome-Wide DNA Methylation and Gene Expression in Patients with Indolent Systemic Mastocytosis

by Aleksandra Górska, Maria Urbanowicz, Łukasz Grochowalski, Michał Seweryn, Marta Sobalska-Kwapis, Tomasz Wojdacz, Magdalena Lange, Marta Gruchała-Niedoszytko, Justyna Jarczak, Dominik Strapagiel, Magdalena Górska-Ponikowska, Iwona Pelikant-Małecka, Leszek Kalinowski, Bogusław Nedoszytko, Danuta Gutowska-Owsiak and Marek Niedoszytko

Int. J. Mol. Sci. 2023, 24(18), 13910; https://doi.org/10.3390/ijms241813910 - 10 Sep 2023

Cited by 1 | Viewed by 1252

Abstract

Mastocytosis is a clinically heterogenous, usually acquired disease of the mast cells with a survival time that depends on the time of onset. It ranges from skin-limited to systemic disease, including indolent and more aggressive variants. The presence of the oncogenic KIT p. D816V gene somatic mutation is a crucial element in the pathogenesis. However, further epigenetic regulation may also affect the expression of genes that are relevant to the pathology. Epigenetic alterations are responsible for regulating the expression of genes that do not modify the DNA sequence. In general, it is accepted that DNA methylation inhibits the binding of transcription factors, thereby down-regulating gene expression. However, so far, little is known about the epigenetic factors leading to the clinical onset of mastocytosis. Therefore, it is essential to identify possible epigenetic predictors, indicators of disease progression, and their link to the clinical picture to establish appropriate management and a therapeutic strategy. The aim of this study was to analyze genome-wide methylation profiles to identify differentially methylated regions (DMRs) in patients with mastocytosis compared to healthy individuals, as well as the genes located in those regulatory regions. Genome-wide DNA methylation profiling was performed in peripheral blood collected from 80 adult patients with indolent systemic mastocytosis (ISM), the most prevalent subvariant of mastocytosis, and 40 healthy adult volunteers. A total of 117 DNA samples met the criteria for the bisulfide conversion step and microarray analysis. Genome-wide DNA methylation analysis was performed using a MethylationEPIC BeadChip kit. Further analysis was focused on the genomic regions rather than individual CpG sites. Co-methylated regions (CMRs) were assigned via the CoMeBack method. To identify DMRs between the groups, a linear regression model with age as the covariate on CMRs was performed using Limma. Using the available data for cases only, an association analysis was performed between methylation status and tryptase levels, as well as the context of allergy, and anaphylaxis. KEGG pathway mapping was used to identify genes differentially expressed in anaphylaxis. Based on the DNA methylation results, the expression of 18 genes was then analyzed via real-time PCR in 20 patients with mastocytosis and 20 healthy adults. A comparison of the genome-wide DNA methylation profile between the mastocytosis patients and healthy controls revealed significant differences in the methylation levels of 85 selected CMRs. Among those, the most intriguing CMRs are 31 genes located within the regulatory regions. In addition, among the 10 CMRs located in the promoter regions, 4 and 6 regions were found to be either hypo- or hypermethylated, respectively. Importantly, three oncogenes—FOXQ1, TWIST1, and ERG—were identified as differentially methylated in mastocytosis patients, for the first time. Functional annotation revealed the most important biological processes in which the differentially methylated genes were involved as transcription, multicellular development, and signal transduction. The biological process related to histone H2A monoubiquitination (GO:0035518) was found to be enriched in association with higher tryptase levels, which may be associated with more aberrant mast cells and, therefore, more atypical mast cell disease. The signal in the BAIAP2 gene was detected in the context of anaphylaxis, but no significant differential methylation was found in the context of allergy. Furthermore, increased expression of genes encoding integral membrane components (GRM2 and KRTCAP3) was found in mastocytosis patients. This study confirms that patients with mastocytosis differ significantly in terms of methylation levels in selected CMRs of genes involved in specific molecular processes. The results of gene expression profiling indicate the increased expression of genes belonging to the integral component of the membrane in mastocytosis patients (GRM2 and KRTCAP3). Further work is warranted, especially in relation to the disease subvariants, to identify links between the methylation status and the symptoms and novel therapeutic targets. Full article

(This article belongs to the Special Issue The Epigenetic Landscape in Cancer)

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16 pages, 6171 KiB

Open AccessArticle

In Vivo Identification of H3K9me2/H3K79me3 as an Epigenetic Barrier to Carcinogenesis

by Maria Cristina Piro, Valeria Gasperi, Alessandro De Stefano, Lucia Anemona, Claudio Raffaele Cenciarelli, Manuela Montanaro, Alessandro Mauriello, Maria Valeria Catani, Alessandro Terrinoni and Alessandra Gambacurta

Int. J. Mol. Sci. 2023, 24(15), 12158; https://doi.org/10.3390/ijms241512158 - 29 Jul 2023

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Abstract

The highly dynamic nature of chromatin’s structure, due to the epigenetic alterations of histones and DNA, controls cellular plasticity and allows the rewiring of the epigenetic landscape required for either cell differentiation or cell (re)programming. To dissect the epigenetic switch enabling the programming of a cancer cell, we carried out wide genome analysis of Histone 3 (H3) modifications during osteogenic differentiation of SH-SY5Y neuroblastoma cells. The most significant modifications concerned H3K27me2/3, H3K9me2, H3K79me1/2, and H3K4me1 that specify the process of healthy adult stem cell differentiation. Next, we translated these findings in vivo, assessing H3K27, H3K9, and H3K79 methylation states in biopsies derived from patients affected by basalioma, head and neck carcinoma, and bladder tumors. Interestingly, we found a drastic decrease in H3K9me2 and H3K79me3 in cancer specimens with respect to their healthy counterparts and also a positive correlation between these two epigenetic flags in all three tumors. Therefore, we suggest that elevated global levels of H3K9me2 and H3K79me3, present in normal differentiated cells but lost in malignancy, may reflect an important epigenetic barrier to tumorigenesis. This suggestion is further corroborated, at least in part, by the deranged expression of the most relevant H3 modifier enzymes, as revealed by bioinformatic analysis. Overall, our study indicates that the simultaneous occurrence of H3K9me2 and H3K79me3 is fundamental to ensure the integrity of differentiated tissues and, thus, their combined evaluation may represent a novel diagnostic marker and potential therapeutic target. Full article

(This article belongs to the Special Issue The Epigenetic Landscape in Cancer)

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Review

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28 pages, 1961 KiB

Open AccessReview

Epigenetic Dysregulation in MYCN-Amplified Neuroblastoma

by Soraya Epp, Shin Mei Chuah and Melinda Halasz

Int. J. Mol. Sci. 2023, 24(23), 17085; https://doi.org/10.3390/ijms242317085 - 03 Dec 2023

Cited by 1 | Viewed by 1613

Abstract

Neuroblastoma (NB), a childhood cancer arising from the neural crest, poses significant clinical challenges, particularly in cases featuring amplification of the MYCN oncogene. Epigenetic factors play a pivotal role in normal neural crest and NB development, influencing gene expression patterns critical for tumorigenesis. This review delves into the multifaceted interplay between MYCN and known epigenetic modifications during NB genesis, shedding light on the intricate regulatory networks underlying the disease. We provide an extensive survey of known epigenetic mechanisms, encompassing DNA methylation, histone modifications, non-coding RNAs, super-enhancers (SEs), bromodomains (BET), and chromatin modifiers in MYCN-amplified (MNA) NB. These epigenetic changes collectively contribute to the dysregulated gene expression landscape observed in MNA NB. Furthermore, we review emerging therapeutic strategies targeting epigenetic regulators, including histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), and DNA methyltransferase inhibitors (DNMTi). We also discuss and summarize current drugs in preclinical and clinical trials, offering insights into their potential for improving outcomes for MNA NB patients. Full article

(This article belongs to the Special Issue The Epigenetic Landscape in Cancer)

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18 pages, 2050 KiB

Open AccessReview

Insight into the Epigenetics of Kaposi’s Sarcoma-Associated Herpesvirus

by Anusha Srivastava, Ankit Srivastava and Rajnish Kumar Singh

Int. J. Mol. Sci. 2023, 24(19), 14955; https://doi.org/10.3390/ijms241914955 - 06 Oct 2023

Viewed by 1514

Abstract

Epigenetic reprogramming represents a series of essential events during many cellular processes including oncogenesis. The genome of Kaposi’s sarcoma-associated herpesvirus (KSHV), an oncogenic herpesvirus, is predetermined for a well-orchestrated epigenetic reprogramming once it enters into the host cell. The initial epigenetic reprogramming of the KSHV genome allows restricted expression of encoded genes and helps to hide from host immune recognition. Infection with KSHV is associated with Kaposi’s sarcoma, multicentric Castleman’s disease, KSHV inflammatory cytokine syndrome, and primary effusion lymphoma. The major epigenetic modifications associated with KSHV can be labeled under three broad categories: DNA methylation, histone modifications, and the role of noncoding RNAs. These epigenetic modifications significantly contribute toward the latent–lytic switch of the KSHV lifecycle. This review gives a brief account of the major epigenetic modifications affiliated with the KSHV genome in infected cells and their impact on pathogenesis. Full article

(This article belongs to the Special Issue The Epigenetic Landscape in Cancer)

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