ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer

Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL’s partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies. [Display omitted] •AR-V7 profiling in CRPC unveils non-canonical pathways uniquely targeted by AR-V7•ZFX is a crucial partner of AR-V7 promoting non-canonical oncogenic roles of AR-V7•Genes uniquely coregulated by AR-V7 and ZFX promote malignant growth of CRPC cells•Targeting the AR-V7 cofactors ZFX or BRD4 represents a new means for CRPC treatment By cistrome profiling of endogenous androgen receptor (AR) versus an AR splice variant, AR-V7, Cai et al. uncovered non-canonical pathways uniquely targeted by AR-V7 and ZFX, a previously unknown AR-V7 partner. Targeting cofactors (ZFX or BRD4) or non-canonical downstream pathways of AR-V7 provides potential therapeutic ways for treating prostate cancer.