PTGES3 emerges as a key regulator of the androgen receptor in prostate cancer

A poorly characterized protein, historically considered a chaperone or enzyme, may actually play a key role in prostate cancer. In a systematic CRISPR screen, researchers from the Arc Institute at the University of California and the Fred Hutchinson Cancer Center identified PTGES3, known as the third protein of prostaglandin E synthase, as an unexpected regulator of the androgen receptor. This discovery, published on November 5, not only redefines the biological role of PTGES3 in regulating gene expression, but also reveals a promising new target for the treatment of aggressive prostate cancers resistant to current hormonal therapies.

The research team made this connection after creating a fluorescent marker that tracks androgen receptor levels in real time. The androgen receptor is a hormone-sensing protein that normally helps with the development and maintenance of the prostate. Androgen receptor activity is highly enhanced in prostate cancer cells and causes aggressive tumor progression, making it a primary target of current treatments. This tagging innovation allowed researchers to perform genome-wide CRISPR screening to identify which genes are necessary to maintain androgen receptor levels in aggressive prostate cancer cells.

During the study, researchers turned off genes one by one to see what caused the glowing androgen receptor protein to disappear. The screening confirmed the presence of well-known androgen receptor regulators such as HOXB13 and GATA2 – validating the approach – but also revealed unexpected candidates, including PTGES3. Because PTGES3 was the only one of three related prostaglandin-synthesizing enzymes that affected androgen receptor levels, the results suggest that it may not work as thought after all.

Our study illustrates the power of CRISPR approaches to adopt an unbiased quantitative approach to discover something new about a well-studied protein. We were initially interested in identifying enzymes that could regulate androgen receptor biology because they could be drugged, but we ended up with PTGES3, a protein that, as far as we can tell, is not an enzyme and has a profound effect on the androgen receptor.

Luke Gilbert (X: @LukeGilbertSF), senior author, Arc Institute principal investigator and associate professor of urology, UCSF School of Medicine

To further investigate the potential role of PTGES3 in prostate cancer, the research team analyzed patient data and found that those with high PTGES3 expression had significantly worse outcomes when treated with hormone therapy. In mouse studies, suppression of PTGES3 delayed tumor growth and reduced the levels of androgen receptors in tumors, suggesting that it may represent a new therapeutic target for treatment-resistant cancers.

Scientists have shown that in cancer cells, PTGES3 actually works through a dual mechanism: acting as a co-chaperone that helps stabilize the androgen receptor protein in the cell’s cytoplasm, and as a nuclear cofactor that allows the androgen receptor to bind to DNA and turn on target genes. If the androgen receptor drives prostate cancer progression, researchers provide evidence that tumor growth may be aided or even dependent on the help of PTGES3.

“Previous attempts to modulate transcription factor function in therapy have focused on DNA-binding domains and transcription activation domains. On the other hand, less attention has been paid to targeting regulators of transcription factor stability,” says first author Haolong Li, who conducted the work at UCSF and is now an assistant professor at Fred Hutch. “Our study may serve as a template for understanding other important transcription factors in various types of hormone-dependent cancers. There are over 20 transcription factors in future oncology research that could benefit from this approach.”

The research team is currently working to understand the structural details of how PTGES3 interacts with the androgen receptor. Their long-term goal is to develop drugs that target this interaction, potentially using protein degradation strategies that have already shown promise in clinical trials.

The study’s second senior author, Felix Feng, professor of radiation oncology, urology and medicine and vice chair of translational research at the Feng Comprehensive Family Cancer Center. Helen Diller at the University of California, California, died last December. “We miss Feliks very much and hope that this work will become part of his legacy,” says Gilbert.

The research described in this article was supported by the National Institutes of Health, the Prostate Cancer Foundation, the Department of Defense Prostate Cancer Research Program, the Howard Hughes Medical Institute, the Swedish Research Council, the UCSF Benioff Prostate Cancer Research Initiative, and the Arc Institute. Researchers have filed patent applications related to targeting PTGES3.