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.

The ETS Domain Transcription Factor ELK1 Directs a Critical Component of Growth Signaling by the Androgen Receptor in Prostate Cancer Cells

“…Recent reports have demonstrated enrichment of possible ELK1 binding sites in relation to chromatin sites of AR binding (52)(53)(54). The observation that ELK1, fully or in part, supported a substantial proportion (ϳ27%) of all gene activation (direct or indirect) by androgen in PC cells suggests that only a few ARtethering proteins may be adequate to direct AR signaling toward supporting growth.…”

Multifaceted role of EZH2 in breast and prostate tumorigenesis

“…The crosstalk among EZH2, AR, ERG and HDACs upon androgen signaling was reported to promote prostate cancer progression. 117 ERG, together with HDACs and EZH2, modulate the transcriptional output of AR, thereby promoting tumorigenesis.…”

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

“…More recently, the genomic binding profile of AR variants have also been explored and have been shown to compensate for full length AR in an endocrine therapy-like setting [22]. These studies have provided valuable insights in to the molecular biology and function of the AR and have identified several co-activators and corepressors that modulate AR transcriptional activity [23][24][25][26][27][28].…”