Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells. ARv7 expression increases rapidly in response to ENZ, but there is a delay in gaining chromatin binding and transcriptional activity, which is associated with increased chromatin accessibility. AR and nuclear factor I (NFI) motifs are most enriched at more accessible sites, and NFIB/X knockdown greatly diminishes ARv7 function. These findings indicate that ARv7 can drive the AR program but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.
Cell reports. 2024 Dec 21 [Epub ahead of print]
Larysa Poluben, Mannan Nouri, Jiaqian Liang, Shaoyong Chen, Andreas Varkaris, Betul Ersoy-Fazlioglu, Olga Voznesensky, Irene I Lee, Xintao Qiu, Laura Cato, Ji-Heui Seo, Matthew L Freedman, Adam G Sowalsky, Nathan A Lack, Eva Corey, Peter S Nelson, Myles Brown, Henry W Long, Joshua W Russo, Steven P Balk
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA; Eli and Edythe L. Broad Institute, Cambridge, MA, USA., Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA., Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Medical Pharmacology, School of Medicine, Koç University, Istanbul 34450, Turkey; Koç University Research Centre for Translational Medicine (KUTTAM), Koç University, Istanbul 34450, Turkey., Department of Urology, University of Washington School of Medicine, Seattle, WA, USA., Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA., Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ., Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: .