Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer
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
Affiliations
Larysa Poluben
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Mannan Nouri
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Jiaqian Liang
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Shaoyong Chen
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Andreas Varkaris
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Betul Ersoy-Fazlioglu
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Olga Voznesensky
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Irene I. Lee
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
Xintao Qiu
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
Laura Cato
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Ji-Heui Seo
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Matthew L. Freedman
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
Adam G. Sowalsky
Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA
Nathan A. Lack
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
Eva Corey
Department of Urology, University of Washington School of Medicine, Seattle, WA, USA
Peter S. Nelson
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
Myles Brown
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
Henry W. Long
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
Joshua W. Russo
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Steven P. Balk
Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: 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.
