The construction of PTGES3. Credit score: Li et al.
A poorly characterised protein, traditionally considered a chaperon or enzyme, may very well be a key participant in prostate most cancers. In a scientific CRISPR display, scientists from Arc Institute, UCSF, and the Fred Hutchinson Most cancers Heart have recognized PTGES3, referred to as the third prostaglandin E synthase protein, as an sudden regulator of the androgen receptor.
This discovery, printed in Nature Genetics, not solely redefines PTGES3’s organic position in regulating gene expression, but in addition reveals a promising new goal for treating aggressive prostate cancers immune to present hormone therapies.
The analysis group made the affiliation after making a fluorescent tag that tracks androgen receptor ranges in actual time. The androgen receptor is a hormone-sensing protein that usually helps develop and preserve the prostate.
Androgen receptor exercise is extremely amplified in prostate most cancers cells and drives aggressive tumor development, making it a primary goal of present therapies. This tagging innovation allowed scientists to conduct genome-wide CRISPR screens to establish which genes are important for sustaining androgen receptor ranges in aggressive prostate most cancers cells.
In the course of the screens, researchers turned off genes one-by-one to see which triggered the glowing androgen receptor protein to vanish. The screens confirmed well-known androgen receptor regulators like HOXB13 and GATA2––validating the method––but in addition revealed sudden candidates, together with PTGES3.
Since PTGES3 was the one considered one of three associated prostaglandin-synthesizing enzymes to have an effect on androgen receptor ranges, outcomes counsel it might not operate because the enzyme it was considered in spite of everything.
“Our study illustrates the power of CRISPR approaches to take a quantitative unbiased approach to discover something new about a well-studied protein,” says senior writer Luke Gilbert, an Arc Institute Core Investigator and an Affiliate Professor of Urology on the UCSF College of Medication.
“We were initially interested in identifying enzymes that might regulate androgen receptor biology because they’re druggable, but we ended up with PTGES3, a protein that, as far as we can tell, isn’t an enzyme and had a profound effect on the androgen receptor.”
To additional examine PTGES3’s potential position in prostate most cancers, the analysis group analyzed affected person knowledge, revealing individuals with excessive PTGES3 expression had considerably poorer outcomes when handled with hormone remedy. In mouse research, suppressing PTGES3 delayed tumor development and lowered androgen receptor ranges in tumors, suggesting it may signify a brand new therapeutic goal for treatment-resistant cancers.
The researchers demonstrated that in most cancers cells, PTGES3 really works via twin mechanisms: functioning as a co-chaperone that helps stabilize the androgen receptor protein within the cytoplasm of the cell, and as a nuclear co-factor that permits the androgen receptor to bind to DNA and activate its goal genes. If the androgen receptor is driving prostate most cancers development, then the researchers present proof that tumor development could also be supported by, and even depending on PTGES3’s help.
“Previous attempts to modulate transcription factor function for therapy have focused on DNA binding domains and transcription activation domains. Targeting regulators of transcription factor stability, on the other hand, has received less attention,” says first writer Haolong Li, who performed the work at UCSF and is presently an Assistant Professor at Fred Hutch.
“Our study could serve as a template for understanding other important transcription factors across different hormone-driven cancer types. Going forward, there are upwards of 20 transcription factors across oncology research that could benefit from this approach.”
The analysis group is now working to grasp the structural particulars of how PTGES3 interacts with the androgen receptor. Their long-term objective is to develop therapeutics concentrating on this interplay, probably utilizing protein degradation methods already displaying promise in medical trials.
The opposite senior writer on this examine, Felix Feng, Professor of Radiation Oncology, Urology, and Medication, and Vice Chair of Translational Analysis on the UCSF Helen Diller Household Complete Most cancers Heart, handed away final December. “We miss Felix deeply and hope this work is part of his legacy,” says Gilbert.
Extra data:
Genome-scale CRISPR screens establish PTGES3 as a direct modulator of androgen receptor operate in superior prostate most cancers, Nature Genetics (2025). DOI: 10.1038/s41588-025-02388-8.
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