Coordinated Regulation of Polycomb Group Complexes through microRNAs in Cancer

Abstract

Summary Polycomb Repressive Complexes (PRC1 and PRC2) mediated epigenetic regulation is critical for maintaining cellular homeostasis. Members of Polycomb Group (PcG) proteins including EZH2, a PRC2 component, are up-regulated in various cancer types, implicating their role in tumorigenesis. Here, we have identified several microRNAs (miRNAs) that are repressed by EZH2. These miRNAs in turn regulate the expression of PRC1 proteins, BMI1 and RING2. We found that ectopic overexpression of EZH2-regulated miRNAs attenuated cancer cell growth and invasiveness, and abrogated cancer stem cell properties. Importantly, expression analysis revealed an inverse correlation between miRNA and PRC protein levels in cell culture and prostate cancer tissues. Taken together, our data has uncovered a coordinate regulation of PRC1 and PRC2 activities that is mediated by miRNAs.

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

“…Recent research demonstrates that the dysregulation of miRNA expression profiles contributes to the pathogenesis of human malignancies [37][38][39][40] . Because the expression of the miR-29 family is reduced in several cancer tissues as compared with normal tissues, the role of the miR-29 family in cancer is controversial 41,42 .…”

Mechanisms of epigenetic deregulation in lymphoid neoplasms

“…[107][108][109][110][111][112] Moreover, genome-wide miRNA profiling studies in ALL further revealed an EZH2 targeted and aberrantly methylated miRNA signature, suggesting that these cases might benefit from EZH2 inhibition. [107][108][109][110][111]113 Along the same lines, miR-26a and miR-29 are repressed by MYC during lymphomagenesis. 114,115 EZH2 targeting by miR-26a might lead to global deregulation of gene expression, whereas MYC recruits HDAC3 and EZH2 complexes to aberrantly repress miR-29.…”

EED regulates epithelial–mesenchymal transition of cancer cells induced by TGF-β

“…Over-expression of EZH2 was involved in tumor initiation and progression [16]. It was reported that EZH2 could repress the expression of CDH1/E-cadherin and miR-200 family genes possibly through the regulation of H3K27 methylation [12,22]. Moreover, a genome-wide profiling of histone methylation during EMT revealed strong correlations between the dynamic changes of histone methylations and gene expression [23].…”