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

2020 ◽  
Author(s):  
Srinivas R. Viswanathan
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Receptor Signaling ◽  
Androgen Receptor Signaling ◽  
A Genome ◽  
Crispr Screen ◽  
Genome Scale

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

2020 ◽  
Author(s):  
Stephen Tang ◽  
Nebiyou Y. Metaferia ◽  
Marina F. Nogueira ◽  
Maya K. Gelbard ◽  
Sarah Abou Alaiwi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Advanced Prostate Cancer ◽  
Cancer Resistance ◽  
Androgen Receptor Signaling ◽  
Disease States ◽  
A Genome ◽  
Crispr Screen ◽  
Protein Arginine Methyltransferase 1 ◽  
Genome Scale

ABSTRACTAndrogen 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.

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