Cancer DNA methylation: molecular mechanisms and clinical implications

DNA methylation plays a crucial role in the regulation of gene expression and chromatin organization within normal eukaryotic cells. In cancer, however, global patterns of DNA methylation are altered with global hypomethylation of repeat-rich intergenic regions and hypermethylation of a subset of CpG-dense gene-associated regions (CpG islands). Extensive research has revealed the cellular machinery that catalyzes DNA methylation, as well as several large protein complexes that mediate the transcriptional repression of hypermethylated genes. However, research is only just beginning to uncover the molecular mechanisms underlying the origins of cancer-specific DNA methylation. Herein, we present several recent advances regarding these mechanisms and discuss the relationship between histone modifications (i.e., H3K4me2/3, H4K16Ac, H3K9me2/3, H3K27me3, H4K20me3), chromatin-modifying enzymes (G9a, EZH2, hMOF, SUV4-20H), and aberrant DNA methylation. Additionally, the role played by inflammation, DNA damage, and miRNAs in the etiology of aberrant DNA methylation is considered. Finally, we discuss the clinical implications of aberrant DNA methylation and the utility of methylated biomarkers in cancer diagnosis and management.