Epigenetic alteration and microRNA dysregulation in cancer

Abstract

MicroRNAs (miRNAs) play pivotal roles in numerous biological processes, and their dysregulation is a common feature of human cancer. Thanks to recent advances in the analysis of the cancer epigenome, we now know that epigenetic alterations, including aberrant DNA methylation and histone modifications, are major causes of miRNA dysregulation in cancer. Moreover, the list of miRNA genes silenced in association with CpG island hypermethylation is rapidly growing, and various oncogenic miRNAs are now known to be upregulated via DNA hypomethylation. Histone modifications also play important roles in the dysregulation of miRNAs, and histone deacetylation and gain of repressive histone marks are strongly associated with miRNA gene silencing. Conversely, miRNA dysregulation is causally related to epigenetic alterations in cancer. Thus aberrant methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Given that many of the silenced miRNAs appear to act as tumor suppressors through the targeting of oncogenes, re-expression of the miRNAs could be an effective approach to cancer therapy, and unraveling the relationship between epigenetic alteration and miRNA dysregulation may lead to the discovery of new therapeutic targets.

Keywords: CpG island methylation; EZH2; biomarker; histone modification; microRNA; oncomir; tumor suppressor.

FIGURE 1

Epigenetic silencing of miRNA genes in cancer. Example of a miRNA gene with its CpG island. In normal cells, the CpG island is unmethylated, and the chromatin is associated with active histone modifications. In cancer cells, CpG island hypermethylation and repressive histone marks lead to epigenetic silencing of the miRNA gene (left). Alternatively, some miRNA genes are silenced through repressive histone modifications, rather than DNA methylation (right).

FIGURE 2

Dysregulation of miRNAs is causally related to epigenetic alterations in cancer. miRNAs able to negatively regulate DNMTs or EZH2 are frequently downregulated in cancer, which leads to epigenetic silencing of target genes.