期刊
MOLECULAR CELL
卷 72, 期 2, 页码 341-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.08.029
关键词
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资金
- UNC Lineberger Cancer Center Core Support Grant [P30CA016086]
- NIH [P50-CA058223, R01-EY014237, R01-CA215284, R01-CA218600, R01-CA211336]
- Lineberger Professorship
- Kimmel Scholar Award
- V Scholar Award
- Concern Foundation for Cancer Research grant
- UNC Cancer Center Core Support Grant [P30-CA016086]
- DoD Prostate Cancer Research Program [W81XWH-10-1-0701]
- Lymphoma Research Foundation fellowship
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.
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