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

By Stephen Tang, Nebiyou Y. Metaferia, Marina F. Nogueira, Maya K. Gelbard, Sarah Abou Alaiwi, Ji-Heui Seo, Justin H. Hwang, Craig A. Strathdee, Sylvan C Baca, Jiao Li, Shatha AbuHammad, Xiaoyang Zhang, John G Doench, William C. Hahn, David Y. Takeda, Matthew L Freedman, Peter S. Choi, Srinivas R. Viswanathan

Posted 17 Jun 2020
bioRxiv DOI: 10.1101/2020.06.17.156034

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. ### Competing Interest Statement J.G.D. consults for Tango Therapeutics, Maze Therapeutics, Foghorn Therapeutics, and Pfizer. W.C.H. is a consultant for ThermoFisher, Solvasta Ventures, MPM Capital, KSQ Therapeutics, iTeos, Tyra Biosciences, Jubilant Therapeutics, Frontier Medicine and Parexel.

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