Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through the re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR-Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates the recruitment of AR to genomic target sites and the inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. In addition, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.
Bibliographical noteFunding Information:
We warmly thank Matthew Meyerson for helpful discussions and guidance. We are grateful for assistance from the DFCI Molecular Biology Core Facility, the Broad Institute and Dana Farber Cancer Institute Flow Cytometry Core Facilities, and the Broad Institute Genetic Perturbation Platform. This work was supported by the Department of Defense Prostate Cancer Research Program ( W81XWH-17-1-0358 to S.R.V.), the Prostate Cancer Foundation Young Investigator Award (to S.R.V.), the Prostate Cancer Foundation Challenge Award (to M.L.F), the American Cancer Society–AstraZeneca (PF-16-142-01-TBE, to J.H.H.), and the National Institutes of Health /National Cancer Institute ( R00 CA208028 , to P.S.C.; R01 CA193910 and R01 CA204954 to M.L.F.; and U01 CA176058 to W.C.H.). The graphical abstract was generated with BioRender.com .
- CRISPR screen
- androgen receptor
- prostate cancer
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.