A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer.

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.
Competing Interests: Declaration of interests J.G.D. consults for Tango Therapeutics, Maze Therapeutics, Foghorn Therapeutics, and Pfizer. W.C.H. is a consultant for Thermo Fisher Scientific, Solasta Ventures, MPM Capital, KSQ Therapeutics, iTeos, Tyra Biosciences, Function Oncology, RAPPTA Therapeutics, Jubilant Therapeutics, Frontier Medicines, and Calyx. S.R.V. has consulted for MPM Capital and Vida Ventures; his spouse is a co-founder, employee of, and holds equity in Kojin Therapeutics. The spouse of P.S.C. is an employee of Cullinan Oncology. J.H.H. is a consultant for and lends research support to Astrin Biosciences and is a principal investigator for the genitourinary subgroup at Caris Life Sciences.
(Copyright © 2022. Published by Elsevier Inc.)