title: A transcriptional repressor co-regulatory network governing androgen response in prostate cancers.
abstract: Transcriptional corepressors are frequently aberrantly over-expressed in prostate cancers. However, their crosstalk with the Androgen receptor (AR), a key player in prostate cancer development, is unclear. Using ChIP-Seq, we generated extensive global binding maps of AR, ERG, and commonly over-expressed transcriptional corepressors including HDAC1, HDAC2, HDAC3, and EZH2 in prostate cancer cells. Surprisingly, our results revealed that ERG, HDACs, and EZH2 are directly involved in androgen-regulated transcription and wired into an AR centric transcriptional network via a spectrum of distal enhancers and/or proximal promoters. Moreover, we showed that similar to ERG, these corepressors function to mediate repression of AR-induced transcription including cytoskeletal genes that promote epithelial differentiation and inhibit metastasis. Specifically, we demonstrated that the direct suppression of Vinculin expression by ERG, EZH2, and HDACs leads to enhanced invasiveness of prostate cancer cells. Taken together, our results highlight a novel mechanism by which, ERG working together with oncogenic corepressors including HDACs and the polycomb protein, EZH2, could impede epithelial differentiation and contribute to prostate cancer progression, through directly modulating the transcriptional output of AR.
authors.affiliation: Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR, Singapore.
authors.forename: Kern Rei
authors.initials: KR
authors.lastname: Chng
authors.forename: Cheng Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Si Kee
authors.initials: SK
authors.lastname: Tan
authors.forename: Chong
authors.initials: C
authors.lastname: Yang
authors.forename: Shu Zhen
authors.initials: SZ
authors.lastname: Hong
authors.forename: Noel Yan Wei
authors.initials: NY
authors.lastname: Sng
authors.forename: Edwin
authors.initials: E
authors.lastname: Cheung
mesh_terms: D000728:Androgens / Q000096:biosynthesis*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000502:physiology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D000728:Androgens; D012097:Repressor Proteins