Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer
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.
Authors
- Nathan A. Lack (ORCID: https://orcid.org/0000-0001-7399-5844)
- Irene Lee (ORCID: https://orcid.org/0000-0002-5749-9389)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Ji-Heui Seo (ORCID: https://orcid.org/0000-0002-7280-3334)
- Myles A Brown (ORCID: https://orcid.org/0000-0002-8213-1658)
- Olga Voznesensky (ORCID: https://orcid.org/0000-0003-1033-0938)
- Andreas Varkaris (ORCID: https://orcid.org/0000-0001-5776-8844)
- Adam G. Sowalsky (ORCID: https://orcid.org/0000-0003-2760-1853)
- Xintao Qiu (ORCID: https://orcid.org/0000-0002-8560-7017)
- Joshua W. Russo (ORCID: https://orcid.org/0000-0001-5481-0090)
- Henry W. Long (ORCID: https://orcid.org/0000-0001-6849-6629)
- Shaoyong Chen (ORCID: https://orcid.org/0000-0003-0809-8383)
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- Larysa Poluben (ORCID: https://orcid.org/0000-0002-5433-6963)
- Matthew L. Freedman (ORCID: https://orcid.org/0000-0002-0151-1238)
- Steven P. Balk (ORCID: https://orcid.org/0000-0002-4546-7371)
- Mannan Nouri (ORCID: https://orcid.org/0000-0002-7442-9251)
- Betul Ersoy-Fazlioglu (ORCID: https://orcid.org/0000-0002-9410-3427)
- Laura Cato (ORCID: https://orcid.org/0000-0002-7072-4368)
- Jiaqian Liang
Institutions
- Beth Israel Deaconess Medical Center (US)
- Koç University (TR)
- Harvard University (US)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- National Cancer Institute (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-12-21
- DOI
- https://doi.org/10.1016/j.celrep.2024.115089
- Citations
- 9
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 3.77
Funders
- Prostate Cancer Foundation
- American Society of Clinical Oncology
- Movember Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Türkiye Bilimsel ve Teknolojik Araştırma Kurumu
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute
- DOD Prostate Cancer Research Program