Canonical and non-canonical regulatory roles of androgen receptor variant 7 (AR-V7) in prostate cancer

ABSTRACT: The androgen receptor splice variant 7 (AR-V7) lacks the ligand-binding domain; is detected with increased frequency in advanced prostate cancer and is postulated to be one crucial mechanism for disease progression and therapeutic resistance to androgen deprivation in castration–resistant prostate cancer ( CRPC). Targeting AR-V7 or unique downstream targets could provide novel therapeutic approaches for CRPC. Here, we report that, independent of ligand, AR-V7 binds not only to the androgen-responsive element (ARE) sites inducing canonical AR signaling but also to non-canonical target sites where ligand-stimulated full-length AR (AR-FL) does not bind. These AR-V7 “solo” binding sites are mainly found at gene promoters and are co-occupied by a zinc-finger transcription factor ZFX and the co-activator BRD4, both of which physically interact with AR-V7. Consequently, AR-V7 not only recapitulates AR-FL action without androgen but uniquely regulates transcripts correlating with AR-V7 expression in the TCGA prostate cancer cohort. Mechanistically, ZFX appears to function as a pioneer factor for AR-V7 at solo-binding sites and BRD4 inhibitors but not anti-androgens suppress AR-V7 action at solo-binding sites as well as AR-V7-dependent growth. Additionally, knockdown of ZFX, or two downstream targets uniquely co-activated by AR-V7 (ZNF32 and FZD6), also suppressed growth of AR-V7-dependent CRPC cells. AR-V7 directly activated genes differentiate tumor from normal prostate tissues and predict poor prognosis in patients. Thus AR-V7 has both canonical and non-canonical regulatory functions in CRPC, which may provide new therapeutic avenues. Overall design: Examination of the genome-wide binding of full-length androgen receptor (AR-FL), AR-V7, Brd4 and ZFX in an castration-resistant prostate cancer cell line in the presence of different drug treatments.

ORGANISM(S): Homo Sapiens

PROVIDER: GSE95068 | GEO |

REPOSITORIES: GEO