DNA methylation of CpG islands, together with deacetylation of histone and methylation of histone H3 lysines 9 and 27 (K9/K27), can lead to silencing of tumor-suppressor genes. The mechanisms underlying DNA methylation changes in cancer involve alteration of the activity of DNA methyltransferases (DNMTs), inflammation, and viral infection. DNA methylation affects genes involved in cell-cycle checkpoints, apoptosis, angiogenesis, invasion, immune responses, and cellular signaling. Subsets of cancers show DNA methylation of multiple genes, indicating that these tumors have the CpG island methylator phenotype (CIMP). Cancers with CIMP show distinct genetic changes, including microsatellite instability and mutations in the BRAF Ser/Thr kinase gene. Repetitive sequences such as short and long interspersed repeat elements are often hypomethylated in cancer, and are implicated in chromosomal instability. DNA methylation is a reversible phenomenon, and DNMT inhibitors can induce gene expression due to demethylation.
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