Role of DNA demethylation in cancer

Abstract

There is an overwhelming amount of evidence that show that DNA methylation patterns are altered in cancer. In a normal cell, methylation of CpG-rich islands in regulatory regions of genes which confer selective advantage upon cancer cells such as tumor suppressors, adhesion molecules, inhibitors of angiogenesis and repair enzymes results in their transcriptional silencing. In parallel, these genes are globally less methylated in the tumor cell genomes normal counterparts. As compared to regional hypermethylation, the global hypomethylation in cancer cells occurs in sparsely distributed CpG sequences, thus making DNA methylation an important contributor in setting gene expression programs during development. Evidence from research suggests that changes in DNA methylation patterns are involved in human disease through altering normal gene expression programming. With respect to genetic changes aberrant DNA methylation patterns are potentially reversible raising the hope for DNA methylation based therapeutics. This reversal of DNA methylation patterns is accomplished mainly by passive mechanisms which include covalent trapping of DNMTs by cytosine base analogues. Removal of methyl layer could also be occurred by excision of the 5-methyl cytosine base by DNA glycosylase. However, the importance of truly chemically defined direct demethylation on intact DNA is mainly in the regulation of gene expression, development and cell growth, hence it becomes necessary to know the exact biochemical mechanism and the enzymes involved in it. The present study has been carried out keeping this in mind with an objective to study the role of demethylation in cancer and investigate certain candidate genes such as methyl-binding proteins MBD2 and MBD4 for putative demethylase activity.