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.

Oestrogen receptor a (ERa) is key player in the progression of breast cancer. Recently, the cistrome and interactome of ERa were mapped in breast cancer cells, revealing the importance of spatial organization in oestrogenmediated transcription. However, the underlying mechanism of this process is unclear. Here, we show that ERa binding sites (ERBS) identified from the Chromatin Interaction Analysis-Paired End DiTag of ERa are enriched for AP-2 motifs. We demonstrate the transcription factor, AP-2c, which has been implicated in breast cancer oncogenesis, binds to ERBS in a ligand-independent manner. Furthermore, perturbation of AP-2c expression impaired ERa DNA binding, long-range chromatin interactions, and gene transcription. In genome-wide analyses, we show that a large number of AP-2c and ERa binding events converge together across the genome. The majority of these shared regions are also occupied by the pioneer factor, FoxA1. Molecular studies indicate there is functional interplay between AP-2c and FoxA1. Finally, we show that most ERBS associated with long-range chromatin interactions are colocalized with AP-2c and FoxA1. Together, our results suggest AP-2c is a novel collaborative factor in ERa-mediated transcription.