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

Abstract

<jats:p>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 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 recruitment of AR to genomic target sites and inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. Additionally, 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.</jats:p>

Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer

“…In contrast to de novo resistance studies, cell lines with acquired resistance may lead to the discovery of novel resistance mechanisms, but it is challenging to identify the underlying mechanism [ 11 ]. More recently, genome-wide CRISPR-Cas9 screenings allowed the discovery of novel resistance mechanisms [ 24 ]. While these cell lines certainly have their place in the preclinical research landscape, they do not reflect all aspects of the heterogeneous primary tumor biology.…”

EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

“…Among these, epigenetic modifiers that were previously implicated in breast cancer cell fitness such as PRMT5 [58,59], HDAC3 [60], NPM1 [61,62] were depleted in MDA-MB-231 cells serving as positive controls. Similarly, for prostate cancer, KDM1A [63], BRD4 [64], and PRMT1 [65] were depleted in LNCaP cells as well as AR, FOXA1 and NCOA1 [66,67], thus serving as positive controls. In addition, well-known cancer survival genes such as PELP1 and PRMT family members were identified as common hits in all the six cancer cell lines screened by EPIKOL (Figure 2D) [58,59,[68][69][70].…”