ZFX mediates non-canonical oncogenic functions of the androgen receptor splice variant 7 (AR-V7) in castrate-resistant prostate cancer

conducted of RNA-seq and cancer datasets the of and P.W., and analzyed ChlP- seq data under the supervision of D.Z.. L.C., Y.T., Y.E.W., J.S.P., D.Z., H.S.E. and interpreted the data. L.C., 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 (ARE) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL’s partial functions but regulates an additional gene-expression program uniquely via binding to gene promoters rather than ARE enhancers. ARV7 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 ARV7 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.

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