The rise and fall of genomic methylation in cancer

Abstract

Changes in genomic methylation and its significance in carcinogenesis is in the spotlight once again, though the focus is not on the usual suspects, DNA hypermethylation and tumour suppressor gene (TSG) silencing. Several recent reports provide compelling evidence of the relevance of genomic hypomethylation in cancer. These findings provide the best evidence so far that links the loss of DNA methylation and chromosomal instability with cancer development. This review article discusses these recent findings and reflects on the antithetical association between DNA methylation and carcinogenesis and the re-examination of studies performed almost two decades ago. Leukemia (2004) The two sides of genomic methylationThe genome is exquisitely packaged as a physical entity comprising deoxyribonucleic acid that contains the template for genetic information. In eukaryotes, histone and nonhistone proteins package nuclear DNA into nucleosomes and higher order chromatin structures that make up the chromosome. The modification of genomic DNA and the protein components of chromatin regulate critical molecular processes such as transcriptional control, DNA replication and repair, chromosome segregation and genomic stability. The covalent modification of DNA by methylation is one of the best characterized epigenetic changes. [1][2][3][4][5] The events that regulate chromatin structure and transcriptional competence mediated by changes in epigenetic regulation are also beginning to be understood. 5 Yet, the link between genomic methylation and the progression of cancer has been a source of intense controversy for many years. 6 This has led researchers to investigate the biological role of DNA methylation in cancer. Are elevated or reduced genomic methylation patterns associated with cancer progression? The answer appears to be both, at least in different model systems regardless of whether they be losses or gains in the methylation moiety. Hypermethylation of CpG sequences is generally associated with gene silencing and the identification of putative TSGs and the characterization of bona fide genes continues to grow at a rapid pace. 7,8 There is ample evidence that supports a critical role for promoter methylation in oncogenesis in primary as well as cultured tumour cells. 9,10 Indeed, this change in genomic methylation has become pertinent mark in the field of cancer epigenetics. Recent studies disrupting the DNA methyltransferase genes, DNMT1 and DNMT3b, reduce the overall genomic methylation content and alleviate repression of p16INK4a and TIMP3. 11 Somatic knockout of the DNMT3b gene reduces the global methylation levels by 3% and almost 20% when the DNMT1 gene is disrupted. Unexpectedly, double knockouts (DKOs) show complete genomic methylation loss which correlates with the reversal of gene silencing. 11 DNMT1 null cells treated with the demethylating agent, 5-aza 2 0 -deoxycytidine (5adC), show p16 demethylation and gene reactivation. These results present the most compelling demonstration to date of the involvement of ...

Array-based genomic resequencing of human leukemia

“…DNMT3A, together with DNMT3B, has an essential role in de novo methylation of the human genome (Okano et al, 1999), and an aberrant methylation profile (hypermethylation of CpG islands and hypomethylation of other regions) is a hallmark of cancer cells (El-Osta, 2004). Despite a direct linkage between such methylation changes and silencing of tumor-suppressor genes in cancer, the molecular mechanism responsible for such abnormal methylation remains unknown.…”

Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma

“…In particular, hypermethylation of the promoter region is associated with silencing of tumor suppressor/DNA repair genes, transcriptional activation of oncogenes and loss of imprinting in malignant cells [34][35][36]. It is well known that the increased incidence of DNA hypermethylation in the CpG island in the proximal promoter or the first exon of estrogen receptor (ER)-alpha is highly associated with the loss of ER-alpha expression in breast cancers [37,38].…”

“…Local regulation of the DNA methylation status of T-DMRs may depend on the combination of global regulators and other undefined factors involved in the histone modification system [33]. Therefore, the D-DMRs found in uterine leiomyomas may now be thought to arise due to global disruption or globally inappropriate maintenance of T-DMRs.Alterations in regional methylation patterns have been reported to be involved in pathogenesis of malignant tumors [34][35][36]. In particular, hypermethylation of the promoter region is associated with silencing of tumor suppressor/DNA repair genes, transcriptional activation of oncogenes and loss of imprinting in malignant cells [34][35][36].…”

Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy

“…In fact, DNA hypomethylation, an early event in tumorigeneisis, can predispose cells to chromosomal rearrangements and destabiliztion of chromosomal organization. 17,68 In this context, it is noteworthy that methyl deficient diet can lead to both global DNA hypomethylation and localized or regional hypermethylation of genes such as tumor suppressor genes. 33,69 The most accepted concept is to envisage early changes in the hypomethylation of genes such as oncogenes followed by hypermethylation of genes such as tumor suppressor genes during cell transformation or in tumorigenesis, both processes resulting in gene deregulation.…”

“…2 It is remarkable that hypermethylation is absent in the mutated allele, but is always associated with the wild-type allele of a gene. 14 Since numerous reviews on DNA methylation have appeared in the past few years, 2,3,[15][16][17] this review will focus on a novel class of candidate tumor suppressor genes that are silenced by promoter methylation in rodent and human tumors, and their functional, diagnostic and therapeutic implications.…”