CtBP2 modulates the androgen receptor to promote prostate cancer progression

The androgen receptor (AR) is the key driver of both early and advanced prostate cancer (PCa), making a complete understanding of its regulation important. Here we report the identification of multiple AR binding sites in the gene encoding the transcription factor CtBP2, genetic variations of which have been associated to PCa susceptibility. Notably, we found that single-nucleotide polymorphisms in the human CTBP2 gene that were associated with PCa development were correlated with AR enhancer activity. High CtBP2 expression levels correlated with poor prognosis in patients, whereas CtBP2 silencing reduced tumor growth in a mouse xenograft model of human PCa. Consistent with its function as a transcriptional co-repressor, CtBP2 repressed tumor suppressor genes and AR co-repressors in PCa cells, such as NCOR and RIP140, by binding with AR to the promoter-enhancers of these genes. Global gene expression analyses revealed a positive effect on androgen-mediated gene expression, and CtBP2 silencing was found to increase AR interactions with co-repressors that limit histone modification. Overall, our results show how CtBP2 contributes to prostate cancer progression by modulating AR and oncogenic signaling.