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Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer

Li, Haolong ; Melnyk, James E. ; Fu, Becky Xu Hua ; Shrestha, Raunak ; Zhang, Meng ; Sjöström, Martin LU ; Feng, Siyu ; Anderson, Jasmine A. ; Han, Wanting and Chesner, Lisa N. , et al. (2025) In Nature Genetics 57(12). p.3027-3038
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Genetics
volume
57
issue
12
pages
12 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:41193657
  • scopus:105020913666
ISSN
1061-4036
DOI
10.1038/s41588-025-02388-8
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2025.
id
1af00d47-b473-434e-ad54-98fbd728b6ea
date added to LUP
2026-01-13 14:03:30
date last changed
2026-01-14 03:00:08
@article{1af00d47-b473-434e-ad54-98fbd728b6ea,
  abstract     = {{<p>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.</p>}},
  author       = {{Li, Haolong and Melnyk, James E. and Fu, Becky Xu Hua and Shrestha, Raunak and Zhang, Meng and Sjöström, Martin and Feng, Siyu and Anderson, Jasmine A. and Han, Wanting and Chesner, Lisa N. and Shin, Hyun Jin and Farsh, Tatyanah and Suarez, Humberto J. and Nath, Seema and Chou, Jonathan and Das, Rajdeep and Egusa, Emily A. and Calvert, Marsha and Kishishita, Audrey and Barpanda, Abhilash and Zhu, Jun and Maheshwari, Ashutosh and Chen, William S. and Alshalalfa, Mohammed and Winters, Aidan and Hua, Junjie T. and Liu, Tianyi and Davicioni, Elai and Wiita, Arun P. and Stohr, Bradley A. and Siddiqui, Javed and Huang, Bo and Small, Eric J. and Shokat, Kevan M. and Nelson, Peter S. and Quigley, David A. and Wasmuth, Elizabeth V. and Gilbert, Luke A. and Feng, Felix Y.}},
  issn         = {{1061-4036}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{3027--3038}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer}},
  url          = {{http://dx.doi.org/10.1038/s41588-025-02388-8}},
  doi          = {{10.1038/s41588-025-02388-8}},
  volume       = {{57}},
  year         = {{2025}},
}