DNA demethylation and invasive cancer: implications for therapeutics

Abstract

One of the hallmarks of cancer is aberrant DNA methylation, which is associated with abnormal gene expression. Both hypermethylation and silencing of tumour suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. As DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumour suppressor genes. Two cytosine analogues, 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine, were approved by the Food and Drug Administration as antitumour agents in 2004 and 2006 respectively. However, these agents might cause activation of a panel of prometastatic genes in addition to activating tumour suppressor genes, which might lead to increased metastasis. This poses the challenge of how to target tumour suppressor genes and block cancer growth with DNA-demethylating drugs while avoiding the activation of prometastatic genes and precluding the morbidity of cancer metastasis. This paper reviews current progress in using DNA methylation inhibitors in cancer therapy and the potential promise and challenges ahead. LINKED ARTICLESThis article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-11 Abbreviations 5-azaC, 5-azacytidine; 5-azadC, 5-aza-2′-deoxycytidine; FDA, Food and Drug Administration; HDAC, histone deacetylase; SAH, S-adenosyl-homocysteine; SAHA, suberoylanilide hydroxamic acid; SAM, S-adenosyl-methionine Tables of Links DNA methylation overviewDNA methylation is an enzymatically catalysed covalent modification of DNA, occurring typically in the context of cytosine-phosphate-guanine (CpG) dinucleotides. In general, regions with high CpG content, named CpG islands, are demethylated in normal cells, whereas regions with an intermediate or low density of CpGs are differentially methylated in some tissues, but not in others (Bird et al., 1985). Although rarely observed, non-CpG methylation is mainly found in embryonic stem cells (Lister et al., 2009), but its function needs to be further explored. However, non-CpG methylation is abundant in adult brains, and recent data suggest that it plays a role in silencing promoter activity similar to CpG methylation (Guo et al., 2013;Lister et al., 2013). DNA methyltransferases (DNMTs) catalyse the transfer of a methyl group from its donor S-adenosine-methionine (SAM) to the cytosine nucleotide of DNA. Three distinct phylogenic DNMTs were identified in mammals. DNMT1 is a maintenance DNMT, which shows preference for hemimethylated DNA in vitro and faithfully copies DNA methylation in a cytosine-guanine (CG) palindromic dinucleotide from the parental strand to the daughter strand during cell division (Zucker et al., 1985;Flynn et al., 1996;Pradhan et al., 1999;Fatemi et al., 2001). DNMT3a and DNMT3b methylate unmethylated and hemimethylated DNA at an equal rate, which is consistent with a de novo methylation function (Okano et ...

Epigenetic Control of the Tumor Microenvironment

“…Newer studies indicate that CpG methylation within gene bodies can be associated with gene activation [34,35]. DNA methylation is regulated by the activities of DNA methyltransferases (DNMT1, DMNT3a and DMNT3b) and multiple DNA demethylases [36,37]. Numerous investigations have shown that CpG islands of DNA are globally hypomethylated in a number of cancer cell types, and that the aberrant expression of specific genes in cancer cells is in part due to demethylation of normally DNA methylated genes [34,[38][39].…”

Loci-specific differences in blood DNA methylation in HBV-negative populations at risk for hepatocellular carcinoma development

“…Aberrations in DNA methylation patterns, including increase (hypermethylation) in certain regions and decrease (hypomethylation) in others, have been linked to cancer initiation, progression, and metastasis [8,13]. Hypermethylation of tumor suppressor genes linked to transcriptional silencing, and recently reported promoter hypomethylation linked to activation of oncogenes and pro-metastatic genes have been described in tumor tissues from nearly all types of cancer including HCC [8,[14][15][16]. Ethanol intake, for instance, decreases levels of a ubiquitous methyl donor S-adenosylmethionine (SAM) in hepatic cells, which subsequently results in global DNA hypomethylation of the liver tissue, and leads to liver cirrhosis and HCC [6,7].…”

Global DNA hypomethylation coupled to cellular transformation and metastatic ability

“…Cancer metastasis is the spread of tumor cells from the original neoplasm to other organs through angiogenesis, invasion, colonization, and proliferation [30]. 5‐azaC treatment was reported to upregulate the prometastatic genes urokinase plasminogen activator, matrix metalloproteinase 2, metastasis‐associated gene 1, and CXC chemokine receptor 4, which stimulate cancer cell invasiveness and metastasis, in the non‐invasive breast cancer cell line MCF‐7 [31].…”