Epigenetic Regulation of EZH2 and Its Targeted MicroRNAs

Abstract

Polycomb group (PcG) proteins are transcriptional repressors which function to silence expressions of developmental and differentiation genes in eukaryotic cells. PcG proteins assemble into complexes termed Polycomb Repressive Complex (PRC) 1 and 2, and they elicit a cascade of epigenetic silencing events starting from trimethylation of the 27th lysine residue on histone H3 by the core PRC2 protein Enhancer of Zeste Homolog 2 (EZH2). In human cancers, PcG-mediated epigenetic silencing activity is increased as a result of upregulation of EZH2 and other PcG proteins. Consequentially, EZH2 is implicated in cancer development through epigenetic repression of tumor suppressor genes. MicroRNAs (miRNAs) are small, endogenously produced non-coding RNAs which function to negatively regulate the expression of their target mRNAs. MiRNA regulation is widespread and virtually over all cellular processes. In recent years, miRNAs have emerged as critical mediators in cancer pathogenesis. Remarkably, EZH2 can epigenetically silence miRNAs, while miRNAs also exert negative control over EZH2 expression, establishing a self-regulatory loop to reinforce their cancer specific roles. In this chapter, we review the current understanding of EZH2 and its regulated miRNAs in malignancies.