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.
Highlights
Epigenetic alteration and microRNA dysregulation in cancerThanks to recent advances in the analysis of the cancer epigenome, we know that epigenetic alterations, including aberrant DNA methylation and histone modifications, are major causes of miRNA dysregulation in cancer
MicroRNAs are endogenous, small, non-coding singlestranded RNAs about 22 nucleotides in length, which function at the post-transcriptional level as negative regulators of gene expression (He and Hannon, 2004)
Each miRNA negatively regulates its target genes in one of two ways, depending on the degree of complementarity between itself and its target messenger RNAs. miRNAs that bind to mRNA sequences with perfect or nearly perfect complementarity induce the RNA-mediated interference (RNAi) pathway, in which mRNA transcripts are cleaved by a miRNA-associated RNA-induced silencing complex
Summary
Thanks to recent advances in the analysis of the cancer epigenome, we know that epigenetic alterations, including aberrant DNA methylation and histone modifications, are major causes of miRNA dysregulation in cancer. The list of miRNA genes silenced in association with CpG island hypermethylation is rapidly growing, and various oncogenic miRNAs are known to be upregulated via DNA hypomethylation. Histone modifications play important roles in the dysregulation of miRNAs, and histone deacetylation and gain of repressive histone marks are strongly associated with miRNA gene silencing. 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
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