A poorly characterized protein, historically thought to be a chaperone or enzyme, may actually be a key player in prostate cancer. In a systematic CRISPR screen, scientists from Arc Institute , UCSF , and the Fred Hutchinson Cancer Center have identified PTGES3, known as the third prostaglandin E synthase protein as an unexpected regulator of the androgen receptor. This discovery, published November 5 in Nature Genetics , not only redefines PTGES3's biological role in regulating gene expression, but also reveals a promising new target for treating aggressive prostate cancers resistant to current hormone therapies.
The research team made the association after creating a fluorescent tag that tracks androgen receptor levels in real time. The androgen receptor is a hormone-sensing protein that normally helps develop and maintain the prostate. Androgen receptor activity is highly amplified in prostate cancer cells and drives aggressive tumor progression, making it a main target of current treatments. This tagging innovation allowed scientists to conduct genome-wide CRISPR screens to identify which genes are essential for maintaining androgen receptor levels in aggressive prostate cancer cells.
During the screens,researchers turned off genes one-by-one to see which caused the glowing androgen receptor protein to disappear. The screens confirmed well-known androgen receptor regulators like HOXB13 and GATA2––validating the approach––but also revealed unexpected candidates including PTGES3. Since PTGES3 was the only one of three related prostaglandin-synthesizing enzymes to affect androgen receptor levels, results suggest it may not function as the enzyme it was thought to be after all.
"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 author Luke Gilbert (X: @LukeGilbertSF ), an Arc Institute Core Investigator and an Associate Professor of Urology at the UCSF School of Medicine. "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 further investigate PTGES3's potential role in prostate cancer, the research team analyzed patient data, revealing people with high PTGES3 expression had significantly poorer outcomes when treated with hormone therapy. In mouse studies, suppressing PTGES3 delayed tumor growth and reduced androgen receptor levels in tumors, suggesting it could represent a new therapeutic target for treatment-resistant cancers.
The researchers demonstrated that in cancer cells, PTGES3 actually works through dual mechanisms: functioning as a co-chaperone that helps stabilize the androgen receptor protein in the cytoplasm of the cell, and as a nuclear co-factor that allows the androgen receptor to bind to DNA and turn on its target genes. If the androgen receptor is driving prostate cancer progression, then the researchers provide evidence that tumor growth may be supported by, or even dependent on PTGES3's assistance.
"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 author Haolong Li , who conducted the work at UCSF and is currently 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 research team is now working to understand the structural details of how PTGES3 interacts with the androgen receptor. Their long-term goal is to develop therapeutics targeting this interaction, potentially using protein degradation strategies already showing promise in clinical trials.
The other senior author on this study, Felix Feng , Professor of Radiation Oncology, Urology, and Medicine, and Vice Chair of Translational Research at the UCSF Helen Diller Family Comprehensive Cancer Center, passed away last December. "We miss Felix deeply and hope this work is part of his legacy," says Gilbert.
