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.
Nature genetics. 2025 Nov 05 [Epub ahead of print]
Haolong Li, James E Melnyk, Becky Xu Hua Fu, Raunak Shrestha, Meng Zhang, Martin Sjöström, Siyu Feng, Jasmine A Anderson, Wanting Han, Lisa N Chesner, Hyun Jin Shin, Tatyanah Farsh, Humberto J Suarez, Seema Nath, Jonathan Chou, Rajdeep Das, Emily A Egusa, Marsha Calvert, Audrey Kishishita, Abhilash Barpanda, Jun Zhu, Ashutosh Maheshwari, William S Chen, Mohammed Alshalalfa, Aidan Winters, Junjie T Hua, Tianyi Liu, Elai Davicioni, Arun P Wiita, Bradley A Stohr, Javed Siddiqui, Bo Huang, Eric J Small, Kevan M Shokat, Peter S Nelson, David A Quigley, Elizabeth V Wasmuth, Luke A Gilbert, Felix Y Feng
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. ., Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., The UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA, USA., Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA., Department of Biochemistry and Structural Biology, Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA., Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA., Arc Institute, Palo Alto, CA, USA., Veracyte Inc, San Diego, CA, USA., Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Department of Pharmaceutical Chemistry, University of CaliforniaSan Francisco, San Francisco, CA, USA., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. .