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DNA Methylation in Cancer Development and Progression

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 14027

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Special Issue Editors

Prof. Dr. Lorenzo Chiariotti

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Guest Editor

Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Naples, Italy
Interests: DNA methylation; cancer epigenetics; neuroepigenetics
Special Issues, Collections and Topics in MDPI journals

Dr. Rosa Della Monica

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Guest Editor

1. Department of Neuroscience and Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, 80131 Naples, Italy
2. CEINGE Biotecnologie Avanzate, 80145 Naples, Italy
Interests: DNA methylation; brain tumors; cell cycle
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

DNA methylation and histone modifications are crucial mechanisms governing chromatin architecture and genome stability. Epigenetic changes can contribute to the development of numerous diseases including neuro-degenerative, autoimmune diseases, and cancer. In fact, it is well established that the hypermethylation of CpG islands is frequently associated with tumor suppressor silencing. Indeed, numerous studies investigating loci-specific and genome-wide DNA methylation profiles have revealed multiple promoter-associated CpG islands that consistently undergo aberrant DNA hypermethylation during cellular transformation. However, global DNA hypomethylation in cancer is thought to contribute to genomic instability and favors aneuploidy, both common features of cancer genomes. The “epigenetic chaos” that characterize tumor development, should be exhaustively defined. Numerous actors are involved and the role of many of these are still poorly known.

In this Special Issue, “DNA Methylation in Cancer Development and Progression”, we would like to host reports of novel findings as well as reviews of the current knowledge regarding the epigenetic mechanisms involved in cancer transformation and progresses in the characterization of novel epigenetic signatures for diagnostic, prognostic, and therapeutic applications.

Prof. Dr. Lorenzo Chiariotti
Dr. Rosa Della Monica
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

cancer epigenetics
DNA methylation
cancer epigenomics
hydroxymethylation in carcer
DNA methylation and DNA repair
evolution of epigenomic profiles in cancer
epigenetic drugs
DNA methylation markers
chromatin and DNA methylation cross-talk
DNA methylation in liquid biopsy
DNA modification signatures
DNA demethylation
epialleles and cancer
single cell DNA methylation

Published Papers (6 papers)

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Research

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16 pages, 16726 KiB

Open AccessArticle

Identification of a Novel Renal Metastasis Associated CpG-Based DNA Methylation Signature (RMAMS)

by Jürgen Serth, Inga Peters, Olga Katzendorn, Tu N. Dang, Joana Moog, Zarife Balli, Christel Reese, Jörg Hennenlotter, Alexander Grote, Marcel Lafos, Hossein Tezval and Markus A. Kuczyk

Int. J. Mol. Sci. 2022, 23(19), 11190; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911190 - 23 Sep 2022

Cited by 1 | Viewed by 1365

Abstract

Approximately 21% of patients with renal cell cancer (RCC) present with synchronous metastatic disease at the time of diagnosis, and metachronous metastatic disease occurs in 20–50% of cases within 5 years. Recent advances in adjuvant treatment of aggressive RCC following surgery suggest that biomarker-based prediction of risk for distant metastasis could improve patient selection. Biometrical analysis of TCGA-KIRC data identified candidate loci in the NK6 homeobox 2 gene (NKX6-2) that are hypermethylated in primary metastatic RCC. Analyses of NKX6-2 DNA methylation in three gene regions including a total of 16 CpG sites in 154 tumor-adjacent normal tissue, 189 RCC, and 194 metastatic tissue samples from 95 metastasized RCC patients revealed highly significant tumor-specific, primary metastatic-specific, and metastatic tissue-specific hypermethylation of NKX6-2. Combined CpG site methylation data for NKX6-2 and metastasis-associated genes (INA, NHLH2, and THBS4) demonstrated similarity between metastatic tissues and metastatic primary RCC tissues. The random forest method and evaluation of an unknown test cohort of tissues using receiver operator characteristic curve analysis revealed that metastatic tissues can be differentiated by a median area under the curve of 0.86 (p = 1.7 × 10⁻⁸–7.5 × 10⁻³) in 1000 random runs. Analysis of variable importance demonstrated an above median contribution for decision-making of at least one CpG site in each of the genes, suggesting superior informativity for sites annotated to NHLH2 and NKX6-2. Thus, DNA methylation of NKX6-2 is associated with the metastatic state of RCC tissues and contributes to a four-gene-based statistical predictor of tumoral and metastatic renal tissues. Full article

(This article belongs to the Special Issue DNA Methylation in Cancer Development and Progression)

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18 pages, 2620 KiB

Open AccessArticle

Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS)

by Christian Faltus, Angelika Lahnsteiner, Myrto Barrdahl, Yassen Assenov, Anika Hüsing, Olga Bogatyrova, Marina Laplana, Theron Johnson, Thomas Muley, Michael Meister, Arne Warth, Michael Thomas, Christoph Plass, Rudolf Kaaks and Angela Risch

Int. J. Mol. Sci. 2022, 23(18), 10699; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810699 - 14 Sep 2022

Viewed by 2348

Abstract

Changes in DNA methylation identified by epigenome-wide association studies (EWAS) have been recently linked to increased lung cancer risk. However, the cellular effects of these differentially methylated positions (DMPs) are often unclear. Therefore, we investigated top differentially methylated positions identified from an EWAS study. This included a putative regulatory region of NHLRC1. Hypomethylation of this gene was recently linked with decreased survival rates in lung cancer patients. HumanMethylation450 BeadChip array (450K) analysis was performed on 66 lung cancer case-control pairs from the European Prospective Investigation into Cancer and Nutrition Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs identified in these pre-diagnostic blood samples were then investigated for differential DNA methylation in lung tumor versus adjacent normal lung tissue from The Cancer Genome Atlas (TCGA) and replicated in two independent lung tumor versus adjacent normal tissue replication sets with MassARRAY. The EPIC HD top hypermethylated DMP cg06646708 was found to be a hypomethylated region in multiple data sets of lung tumor versus adjacent normal tissue. Hypomethylation within this region caused increased mRNA transcription of the closest gene NHLRC1 in lung tumors. In functional assays, we demonstrate attenuated proliferation, viability, migration, and invasion upon NHLRC1 knock-down in lung cancer cells. Furthermore, diminished AKT phosphorylation at serine 473 causing expression of pro-apoptotic AKT-repressed genes was detected in these knock-down experiments. In conclusion, this study demonstrates the powerful potential for discovery of novel functional mechanisms in oncogenesis based on EWAS DNA methylation data. NHLRC1 holds promise as a new prognostic biomarker for lung cancer survival and prognosis, as well as a target for novel treatment strategies in lung cancer patients. Full article

(This article belongs to the Special Issue DNA Methylation in Cancer Development and Progression)

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11 pages, 1503 KiB

Open AccessArticle

Lack of Major Genome-Wide DNA Methylation Changes in Succinate-Treated Human Epithelial Cells

by Wei Cui, Zhijun Huang and Gerd P. Pfeifer

Int. J. Mol. Sci. 2022, 23(10), 5663; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105663 - 18 May 2022

Cited by 1 | Viewed by 1685

Abstract

The tricarboxylic acid (TCA) metabolite, succinate, is a competitive inhibitor of dioxygenase enzymes that require alpha ketoglutarate as a cofactor. One family of dioxygenases are the ten-eleven translocation (TET) proteins, which oxidize 5-methylcytosine to promote DNA demethylation. Inhibition of DNA demethylation is expected to lead to DNA hypermethylation, at least at genomic regions at which TET proteins are engaged. We treated human bronchial epithelial cells with succinate for five days and confirmed its effect on TET protein function by observing diminished formation of 5-hydroxymethylcytosine, the first oxidation product of the TET enzymatic reaction. We then analyzed global DNA methylation patterns by performing whole-genome bisulfite sequencing. Unexpectedly, we did not observe differentially methylated regions (DMRs) that reached genome-wide statistical significance. We observed a few regions of clustered DNA hypomethylation, which was also not expected based on the proposed mechanisms. We discuss potential explanations for our observations and the implications of these findings for tumorigenesis. Full article

(This article belongs to the Special Issue DNA Methylation in Cancer Development and Progression)

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9 pages, 1771 KiB

Open AccessArticle

ESR1 Methylation Measured in Cell-Free DNA to Evaluate Endocrine Resistance in Metastatic Breast Cancer Patients

by Manouk K. Bos, Teoman Deger, Stefan Sleijfer, John W. M. Martens and Saskia M. Wilting

Int. J. Mol. Sci. 2022, 23(10), 5631; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105631 - 18 May 2022

Cited by 4 | Viewed by 1906

Abstract

ESR1 methylation was proposed as mechanism for endocrine resistance in metastatic breast cancer patients. To evaluate its potential as a minimally invasive biomarker, we investigated the feasibility of measuring ESR1 methylation in cell-free DNA (cfDNA) and its association with endocrine resistance. First, we provided evidence that demethylation in vitro restores ER expression. Subsequently, we found that ESR1 methylation in cfDNA was not enriched in endocrine-resistant versus endocrine-sensitive patients. Interestingly, we found a correlation between ESR1 methylation and age. Publicly available data confirm an age-related increase in ESR1 methylation in leukocytes, confounding the determination of the ESR1 methylation status of tumors using cfDNA. Full article

(This article belongs to the Special Issue DNA Methylation in Cancer Development and Progression)

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15 pages, 3163 KiB

Open AccessArticle

DNA Hypomethylation Is Associated with the Overexpression of INHBA in Upper Tract Urothelial Carcinoma

by Chien-Chang Kao, Yin-Lun Chang, Hui-Ying Liu, Sheng-Tang Wu, En Meng, Tai-Lung Cha, Guang-Huan Sun, Dah-Shyong Yu and Hao-Lun Luo

Int. J. Mol. Sci. 2022, 23(4), 2072; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042072 - 13 Feb 2022

Cited by 4 | Viewed by 2351

Abstract

Urothelial carcinoma includes upper urinary tract cancer (UTUC) and bladder cancer. Although nephroureterectomy is the standard treatment for UTUC, the recurrence rate is approximately half and the tumor is associated with poor prognoses. Metastases are the most devastating and lethal clinical situation in urothelial carcinoma. Despite its clinical importance, few potential diagnostic biomarkers are suitable for early UC detection. We compared high-stage/high-grade urothelial carcinoma tissues to adjacent normal urothelial tissues using methyl-CpG binding domain protein capture for genome-wide DNA methylation analysis. Based on our findings, inhibin βA (INHBA) might be associated with carcinogenesis and metastasis. Further, clinical UC specimens had significant INHBA hypomethylation based on pyrosequencing. INHBA was detected by real-time PCR and immunohistochemistry staining, and was found to be highly expressed in clinical tissues and cell lines of urothelial carcinoma. Further, INHBA depletion was found to significantly reduce BFTC-909 cell growth and migration by INHBA-specific small interfering RNA. Interestingly, a positive correlation was found between SMAD binding and extracellular structure organization with INHBA using gene set enrichment analysis and gene ontology analysis. Together, these results are the first evidence of INHBA promoter hypomethylation and INHBA overexpression in UTUC. INHBA may affect urothelial carcinoma migration by reorganizing the extracellular matrix through the SMAD pathway. Full article

(This article belongs to the Special Issue DNA Methylation in Cancer Development and Progression)

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Review

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15 pages, 1742 KiB

Open AccessReview

MGMT and Whole-Genome DNA Methylation Impacts on Diagnosis, Prognosis and Therapy of Glioblastoma Multiforme

by Rosa Della Monica, Mariella Cuomo, Michela Buonaiuto, Davide Costabile, Raduan Ahmed Franca, Marialaura Del Basso De Caro, Giuseppe Catapano, Lorenzo Chiariotti and Roberta Visconti

Int. J. Mol. Sci. 2022, 23(13), 7148; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137148 - 27 Jun 2022

Cited by 20 | Viewed by 3593

Abstract

Epigenetic changes in DNA methylation contribute to the development of many diseases, including cancer. In glioblastoma multiforme, the most prevalent primary brain cancer and an incurable tumor with a median survival time of 15 months, a single epigenetic modification, the methylation of the O⁶-Methylguanine-DNA Methyltransferase (MGMT) gene, is a valid biomarker for predicting response to therapy with alkylating agents and also, independently, prognosis. More recently, the progress from single gene to whole-genome analysis of DNA methylation has allowed a better subclassification of glioblastomas. Here, we review the clinically relevant information that can be obtained by studying MGMT gene and whole-genome DNA methylation changes in glioblastomas, also highlighting benefits, including those of liquid biopsy, and pitfalls of the different detection methods. Finally, we discuss how changes in DNA methylation, especially in glioblastomas bearing mutations in the Isocitrate Dehydrogenase (IDH) 1 and 2 genes, can be exploited as targets for tailoring therapy. Full article

(This article belongs to the Special Issue DNA Methylation in Cancer Development and Progression)

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