Figure 1. Molecular mechanism of action of EZH2. (A) Polycomb dependent mechanism—Role in transcriptional repression. EZH2 functions as a part of mammalian PRC2 core complex consisting of EZH1/2, SUZ12, EED and RbAp46/48 (also called RBBP7/4. When recruited to the target gene promoter it catalyses the di/tri- methylation of Histone 3 at lysine 27 (H3K27me3), resulting in chromatin compaction and inaccessibility of promoter region to RNA Pol II and other proteins of the transcription machinery, which ultimately repress transcription. H3K27me3 mark also serves as a docking site for binding of PRC1 complex containing Bmi1, Ring1a, Ring1b, HPH1, HPH2, NSPC1, MEL18 and CBX proteins (-2, 4, 6, 7, 8). PRC1 catalysed mono-ubiquitination of Histone 2A at lysine 119 further contributes to target gene silencing. (B) Polycomb independent mechanism—Role in transcriptional activation. (1) In prostate cancer cells, Akt-1 mediated phosphorylation of EZH2 at Serine-21 decreases the H3K27me3 activity of EZH2. But phosphorylated EZH2 can function independent of other PRC2 proteins and may methylate androgen receptor at lysine 630 and 632, which can enhance its transcriptional activity. This is a potential mechanism for EZH2 mediated transcriptional activation via methylation of androgen receptor or other androgen receptor associated proteins (X or Y). (2) When over-expressed in ER-positive, luminal like MCF-7 breast cancer cells, EZH2 functions as a transcriptional activator by acting as a bridge to physically link ERα and Wnt signaling components β-catenin and TCF, on the Cyclin B1 and c-Myc promoters. EZH2 also associates with Mediator complex through its domain II independent of the SET domain involved in HMTase activity and enhance transcription by its interaction with RNA polymerase II. In ER-negative, basal like MDA-MB-231 cells, EZH2 forms a ternary complex with NF-kB components RelA and RelB and activates transcription of NF- kB target genes such as TNF, IL6.