Epigenetic Silencing of miR-203 by the Polycomb Group Protein EZH2 Promotes an Aggressive Cancer Phenotype
Pandhi, Mithil B.
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Enhancer of Zeste Homolog 2 (EZH2) is a transcriptional repressor known to silence target genes during development by histone methyl transferase (HMTase) activity and DNA methyl transferase (DNMT) recruitment. EZH2 is overexpressed in multiple cancers and has been shown to promote cancer initiation and progression both in vitro and in vivo, but the underlying mechanism behind EZH2-mediated promotion of oncogenesis and tumor aggressiveness remains unclear. Utilizing microRNA (miRNA) expression profiling, this study identified a putative tumor suppressor, microRNA - 203 (miR-203), as an EZH2 regulated miRNA. Specifically, we demonstrated that epigenetic silencing of miR-203 in breast and prostate cancer is attributed to DNA methylation by EZH2-recruited DNMTs. Quantative real-time PCR (qRT - PCR) shows that EZH2 knockdown by RNA .. interference (RNAi) and use of the DNMT inhibitor 5-aza upregulated miR-203 expression in the prostate and breast cancer cell lines, PC3 and BT-549. We also report that miR-203 inhibited growth and invasion in BT-549 cells. Notably, qRT-PCR shows that miR-101 overexpression upregulated miR-203 expression in the breast and prostate cancer cell lines, SKBr3 and DU145. qRT-PCR analysis of a human prostate cancer cohort revealed that EZH2 expression is inversely correlated with miR-101 and miR-203 expression during prostate cancer progression. Taken together, we propose a novel model by which miR-101 downregulation allows EZH2 overexpression in cancer, leading to the epigenetic silencing of miR-203 and the promotion of an aggressive cancer phenotype. Potential therapeutic application of this model involves the reintroduction of miR-101 and miR-203 into tumors, and may revert tumors to a less aggressive phenotype.