DNA demethylation and invasive cancer: implications for therapeutics

Abstract

One of the hallmarks of cancer is aberrant DNA methylation, which is associated with abnormal gene expression. Both hypermethylation and silencing of tumour suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. As DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumour suppressor genes. Two cytosine analogues, 5-azacytidine (Vidaza) and 5-aza-2'-deoxycytidine, were approved by the Food and Drug Administration as antitumour agents in 2004 and 2006 respectively. However, these agents might cause activation of a panel of prometastatic genes in addition to activating tumour suppressor genes, which might lead to increased metastasis. This poses the challenge of how to target tumour suppressor genes and block cancer growth with DNA-demethylating drugs while avoiding the activation of prometastatic genes and precluding the morbidity of cancer metastasis. This paper reviews current progress in using DNA methylation inhibitors in cancer therapy and the potential promise and challenges ahead.

Figure 1

Combinatory effect of demethylating drugs and demethylating inhibitor. DNMTs inhibitors (5-azaC and 5-azadC) target tumour suppressor and prometastatic genes by demethylating promoters and inducing their expression. This effect can be compensated by combining DNMT inhibitors with a demethylating inhibitor (SAM), which causes prometastatic gene-specific methylation and subsequent down-regulation in gene expression without targeting tumour suppressor genes (Chik et al., 2014). Filled (black) circles correspond to methylated Cs; unfilled (white) circles correspond to demethylated Cs.