Dna Hypomethylation In Cancer Cells

Abstract

DNA hypomethylation was the initial epigenetic abnormality recognized in human tumors. However, for several decades after its independent discovery by two laboratories in 1983, it was often ignored as an unwelcome complication, with almost all of the attention on the hypermethylation of promoters of genes that are silenced in cancers (e.g., tumor-suppressor genes). Because it was subsequently shown that global hypomethylation of DNA in cancer was most closely associated with repeated DNA elements, cancer linked-DNA hypomethylation continued to receive rather little attention. DNA hypomethylation in cancer can no longer be considered an oddity, because recent highresolution genome-wide studies confirm that DNA hypomethylation is the almost constant companion to hypermethylation of the genome in cancer, just usually (but not always) in different sequences. Methylation changes at individual CpG dyads in cancer can have a high degree of dependence not only on the regional context, but also on neighboring sites. DNA demethylation during carcinogenesis may involve hemimethylated dyads as intermediates, followed by spreading of the loss of methylation on both strands. In this review, active demethylation of DNA and the relationship of cancer-associated DNA hypomethylation to cancer stem cells are discussed. Evidence is accumulating for the biological significance and clinical relevance of DNA hypomethylation in cancer, and for cancer-linked demethylation and de novo methylation being highly dynamic processes. Keywordscancer; DNA methylation; DNA repeats; genomic sequencing; hypermethylation; hypomethylation DNA hypomethylation: a ubiquitous feature of carcinogenesisThe first-described epigenetic changes in human cancer were losses of DNA methylation (m 5 C residues replaced by unmethylated C residues) reported in 1983. We observed this alteration of DNA methylation throughout the genome in various cancers versus a wide variety of normal tissues [1], and Feinberg and Vogelstein described hypomethylation of a few cancerirrelevant gene regions in colon adenocarcinomas versus normal colonic epithelium [2,3]. It was apparent that metastases were even more susceptible to cancer-linked DNA In memoriam: This article is dedicated to the memory of Charles Gehrke, PhD and Professor of Biochemistry, University of Missouri, Columbia. His expertise in analytical biochemistry and gracious willingness to collaborate with me, starting in 1979, when I was very much his junior, were critical to launching my career in the then nonexistent field of cancer epigenetics [1,84].

A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes

“…Our observation of the presence of genome-wide hypomethylated regions alongside promoter hypermethylation (Fig. 2) corroborates pervious study in other cancers (19). Although the role of global hypomethylation is unclear, several animal experiments using DNA methylation inhibitors (39,40) are indicative of its involvement in oncogenesis and tumor progression.…”

“…Cytosine methylation alters gene expression and thus plays an important role in other biologic processes, such as embryonic development, imprinting, and X-chromosome inactivation (17,18). Cancer development is characterized by two major DNA methylation changes, hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes (making them inactive) and global hypomethylation leading to activation of oncogenes and transposons (19). By conducting genome-wide methylation studies, one can identify potential DNA methylation markers for early cancer detection.…”

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

“…These results, which are ostensibly in contrast with the classically described global hypomethylation changes in cancer and aging, might potentially arise from the limitations of our study. As the methylation arrays used in our analyses mainly interrogate genetic elements and do not include repeated DNA, which covers a substantial fraction of the genome and frequently loses DNA methylation in tumors and aged cells, the genome‐wide landscape may be different (Ehrlich, 2009). Nonetheless, epigenetic signatures have been successfully derived previously using array technology (Fernández et al., 2015; Rakyan et al., 2010; Teschendorff et al., 2010) and our results are in line with recent studies which report no global decreases in DNA hypomethylation with aging in diverse mouse tissues, such as liver (Cole et al., 2017; Hahn et al., 2017), hippocampus (Masser et al., 2017), or hematopoietic stem cells (Beerman et al., 2013; Sun et al., 2014), thus strengthening the validity of our observations.…”

“…While this molecular alteration preferentially occurs at gene bodies, intergenic DNA regions, and repeated DNA elements (Ehrlich, 2009) and is proposed to be associated with chromosomal instability, reactivation of transposable elements, and loss of genomic imprinting, its precise functional role in cancer development is still poorly understood (Rodríguez‐Paredes & Esteller, 2011). Intriguingly, global loss of genomic DNA methylation has also been reported during the aging and senescence process (Cruickshanks et al., 2013; Fraga & Esteller, 2007).…”

Epigenetic regulation mechanisms of microRNA expression

“…In some pathological conditions, such as human cancers, two epigenetic events have been observed (35): global hypomethylation of the CpG residues that do not form a CpG island is linked to genomic instability, which may take the form of activation of mitotic recombination or activation of transposons (36,37); and hypermethylation of promoter areas, especially CpG islands, associated with the corresponding silencing of tumor suppressor genes (38,39). miRNA genes have been frequently found in the cancer-associated genomic regions (40) and can play two opposing roles in this disease, either as oncogenes or as tumor suppressors (24).…”