Genome-scale genetic screening identifies PRMT1 as a critical vulnerability in castration-resistant prostate cancer

ABSTRACT

Androgen receptor (AR) signaling is the central driver of prostate cancer growth and progression across disease states, including in most cases of castration-resistant prostate cancer (CRPC). While next-generation AR antagonists and androgen synthesis inhibitors are effective for a time in CRPC, tumors invariably develop resistance to these agents, commonly through mechanisms resulting in the overexpression of AR or the production of constitutively active AR splice variants (e.g. AR-V7). Improved mechanistic understanding of the factors that modulate AR expression and signaling may reveal additional therapeutic intervention points in CRPC. Here, we leverage genome-scale CRISPR/Cas9 genetic screening to systematically identify regulators of AR/AR-V7 expression. We identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling that regulates recruitment of AR to genomic target sites. PRMT1 suppression globally perturbs the expression and splicing of AR target genes and inhibits the proliferation and survival of AR-positive prostate cancer cells. Genetic or pharmacologic inhibition of PRMT1 reduces AR binding at lineage-specific enhancers, which leads to decreased expression of key oncogenes, including AR itself. CRPC cells displaying activated AR signaling due to overexpression of AR or AR-V7 are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a critical regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 as a promising new therapeutic strategy in CRPC.