All authors read and approved the final manuscript. COMPETING INTERESTS All authors declared no competing interests. ACKNOWLEDGMENTS This work was supported in part by the U.S. transcription.17 A more recent work from the same group further demonstrated that coREST, an important LSD1-recruiting protein, cooccupies at the ARE-containing enhancers with LSD1.32 This study suggests that the ligand-activated AR recruits REST/coREST/LSD1-dependent repressive complex to the AR-regulated enhancers during target genes repression.32,33 Enhancer of zeste homolog 2 (EZH2) and histone methylation Polycomb repression complex 2 (PRC2), consisted of core subunits suppressor of zeste 12 (SUZ12), embryonic ectoderm development (EED), and EZH2, plays important roles in maintaining embryonic stem cell identity through epigenetic silencing of a large cohort of developmental regulators.34 EZH2 is the enzymatic subunit of PRC2 that catalyzes histone H3 lysine 27 trimethylation (H3K27me3), a reported mark for repressive histone environment.35,36 We have recently reported that EZH2 also plays a polycomb- and methylation-independent role in gene activation, one of its targets being AR, potentiating its function in PCa.37 is among the most upregulated genes in aggressive PCa and its expression is inversely correlated with PCa clinical outcomes.38 behaves as Rabbit Polyclonal to FGFR1 Oncogene Partner a bona fide oncogene as its overexpression promotes prostate tumorigenesis while its depletion leads to cellular senescence and halts tumor progression.39 EZH2 has recently been shown to coordinate with AR on transcriptional repression. Through ChIP-seq analysis of the key transcription factors and histone marks, our group identified an integrative transcriptional network involving AR, EZH2, and ETS-related gene-1 (ERG1) in PCa cells.16 ERG belongs to the ETS family of transcription factors and is frequently fused with the 5 untranslated region of the gene in PCa.40 We showed that ERG cooccupies with AR on many ARE-containing genomic loci to inhibit gene expression, which may be mediated, at least partially, by direct induction of EZH2 expression and recruitment to the target sites for epigenetic silencing. Further, integrating genome-wide AR localization data with androgen-induced gene expression data, we have identified a large number of genes whose expression is directly inhibited by AR but can be rescued through EZH2 inhibition.18,41,42 Collectively, our data establish that EZH2 facilitates AR-transcriptional repression through catalyzing H3K27me3. An additional report from an independent research group confirms the importance of AR-centered coregulatory network, which wires in ERG and EZH2, in the gene repressive program.43 Chng and colleagues Pitolisant oxalate further identified the collaboration between HDAC2/3 and EZH2, as both enzymes were shown to be recruited to the AR target genes by AR-ERG corepressive complex. HDACs probably cooperate with EZH2 through the removal of acyl groups H3K27ac, which primes H3K27 for subsequent methylation by EZH2. Retinoblastoma protein (Rb) and E2F family transcription factors A recent study exhibited that AR contributes to direct repression of the genes involved in DNA replication in PCa through cooperation with Rb.44 Gao and colleagues revealed that acute stimulation of AR rapidly suppresses expression of the proliferative Pitolisant oxalate genes, such as Minichromosome complex maintenance component 7 (promoter and recruits HDAC1 based repressive Pitolisant oxalate complexE-cadherin (CDHE) is an epithelial cell surface molecule, which stabilizes cellCcell adhesion. CDHE inhibits EMT and prevents metastatic dissemination?enhancer regionVinculin (VCL), a cytoskeleton protein important for stabilization of the cell-to-cell and cell-to-matrix contacts. Loss of VCL promotes metastases?promoter and recruits EZH2 that metabolizes repressive trimethylation of H3K27NOV inhibits prostate cancer growth. NOV binds to the N-terminus of AR and.