Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer
The androgen receptor (AR) is a critical driver of prostate cancer (PCa). Here, to study regulators of AR protein levels and oncogenic activity, we developed a live-cell quantitative endogenous AR fluorescent reporter. Leveraging this AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators, including HOXB13 and GATA2, and also unexpected top hits including PTGES3-a poorly characterized gene in PCa. PTGES3 repression resulted in loss of AR protein, cell-cycle arrest and cell death in AR-driven PCa models. Clinically, analysis of PCa data demonstrates that PTGES3 expression is associated with AR-directed therapy resistance. Mechanistically, we show PTGES3 binds directly to AR, regulates AR protein stability and is necessary for AR function in the nucleus at AR target genes. PTGES3 represents a potential therapeutic target for overcoming known mechanisms of resistance to existing AR-directed therapies in PCa.
Authors
- Emily A. Egusa (ORCID: https://orcid.org/0000-0003-2017-5708)
- Becky Xu Hua Fu (ORCID: https://orcid.org/0000-0002-3095-2956)
- Hyun Jin Shin (ORCID: https://orcid.org/0000-0002-3563-8042)
- Siyu Feng
- Eric Jay Small (ORCID: https://orcid.org/0000-0003-3191-6268)
- J. A. Anderson (ORCID: https://orcid.org/0009-0006-7791-7206)
- Elai Davicioni (ORCID: https://orcid.org/0000-0001-9136-099X)
- Humberto J. Suarez
- Seema Nath (ORCID: https://orcid.org/0000-0002-8362-1165)
- Jonathan Chou (ORCID: https://orcid.org/0000-0003-1258-0391)
- Bo Huang (ORCID: https://orcid.org/0000-0003-1704-4141)
- Felix Yi-Chung Feng (ORCID: https://orcid.org/0000-0002-0963-7687)
- Rajdeep Das (ORCID: https://orcid.org/0000-0002-1041-4931)
- Mohammed Alshalalfa (ORCID: https://orcid.org/0000-0001-8405-3035)
- William S. Chen (ORCID: https://orcid.org/0000-0002-3717-670X)
- Luke A. Gilbert (ORCID: https://orcid.org/0000-0001-5854-0825)
- Raunak Shrestha (ORCID: https://orcid.org/0000-0002-1144-1413)
- Martin Sjöström (ORCID: https://orcid.org/0000-0002-2629-9966)
- Bradley A. Stohr (ORCID: https://orcid.org/0000-0002-5836-2624)
- David A. Quigley (ORCID: https://orcid.org/0000-0002-4726-1473)
- James E. Melnyk (ORCID: https://orcid.org/0000-0003-1915-8089)
- Audrey Kishishita (ORCID: https://orcid.org/0000-0002-1984-222X)
- Arun P. Wiita (ORCID: https://orcid.org/0000-0002-7465-6964)
- Lisa N. Chesner (ORCID: https://orcid.org/0009-0007-2779-8824)
- Meng Zhang (ORCID: https://orcid.org/0000-0003-1042-6294)
- Jun Zhu (ORCID: https://orcid.org/0000-0003-2553-1337)
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- Elizabeth V. Wasmuth (ORCID: https://orcid.org/0000-0003-1474-4935)
- Haolong Li (ORCID: https://orcid.org/0000-0002-8628-9698)
- Wanting Han (ORCID: https://orcid.org/0000-0002-2173-3647)
- Kevan M. Shokat (ORCID: https://orcid.org/0000-0001-8590-7741)
- Abhilash Barpanda (ORCID: https://orcid.org/0000-0001-8158-4949)
- Tatyanah Farsh (ORCID: https://orcid.org/0009-0000-8058-1033)
- Tianyi Liu (ORCID: https://orcid.org/0000-0003-2443-9299)
- Junjie T. Hua (ORCID: https://orcid.org/0000-0002-1197-1174)
- Ashutosh Maheshwari (ORCID: https://orcid.org/0000-0002-7107-0933)
- Marsha Calvert
- Javed Siddiqui (ORCID: https://orcid.org/0009-0004-8251-4829)
Institutions
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Howard Hughes Medical Institute (US)
- Emory University (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of California, San Francisco (US)
- Lund University (SE)
- University of Michigan (US)
- American Research Center in Egypt (US)
- Fred Hutch Cancer Center (US)
- University of California San Francisco Medical Center (US)
- Veracyte (United States) (US)
- Chan Zuckerberg Initiative (United States) (US)
- Palo Alto Institute (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Arc Research Institute
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1038/s41588-025-02388-8
- Citations
- 2
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- Prostate Cancer Foundation
- Cancer Prevention and Research Institute of Texas
- Cancerfonden
- Vetenskapsrådet
- Svenska Läkaresällskapet
- National Institutes of Health
- University of California, San Francisco
- Stand Up To Cancer
- National Cancer Institute
- DOD Prostate Cancer Research Program