The Role of DNA Hypermethylation and Demethylation in Cancer and Cancer Therapy

Methylation of DNA is known to be an important mechanism of gene regulation. A hallmark of cancer is the deregulation of the DNA methylation machinery and aberrant DNA methylation patterns ¹. In vertebrate genomes, a large fraction of the CG dinucleotide sequence is modified by methylation in gene- and tissuespecific patterns ². Methylation of critical regulatory regions silences gene expression; loss of methylation is associated with gene activation ³. Because cancer progression requires many changes in the normal program of gene expression, it stands to reason that aberrations in DNA methylation play a critical role in the changes in gene expression involved in cancer progression and metastasis. Methylation changes in DNA play a role very similar to that of genetic mutations in cancer; however, unlike a genetic alteration, DNA methylation is potentially reversible with pharmacologic intervention. The DNA methylation machinery was therefore proposed—almost a decade and a half ago—to be an attractive anticancer target ⁴.