| Title | ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | Cai L, Tsai Y-H, Wang P, Wang J, Li D, Fan H, Zhao Y, Bareja R, Lu R, Wilson EM, Sboner A, Whang YE, Zheng D, Parker JS, H Earp S, Wang GGreg |
| Journal | Mol Cell |
| Volume | 72 |
| Issue | 2 |
| Pagination | 341-354.e6 |
| Date Published | 2018 Oct 18 |
| ISSN | 1097-4164 |
| Keywords | Alternative Splicing, Animals, Carcinogenesis, Cell Differentiation, Cell Line, Cell Line, Tumor, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, HEK293 Cells, Hepatocyte Nuclear Factor 3-alpha, Humans, Kruppel-Like Transcription Factors, Male, Mice, Mice, Inbred NOD, Mice, SCID, Nuclear Proteins, Oncogenes, Promoter Regions, Genetic, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen |
| Abstract | 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. |
| DOI | 10.1016/j.molcel.2018.08.029 |
| Alternate Journal | Mol Cell |
| PubMed ID | 30270106 |
| PubMed Central ID | PMC6214474 |
| Grant List | R01 CA215284 / CA / NCI NIH HHS / United States R01 CA211336 / CA / NCI NIH HHS / United States P30 CA016086 / CA / NCI NIH HHS / United States P50 CA058223 / CA / NCI NIH HHS / United States R01 EY014237 / EY / NEI NIH HHS / United States P30 ES010126 / ES / NIEHS NIH HHS / United States R01 CA218600 / CA / NCI NIH HHS / United States |