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

Stephen Tang; Vidyalakshmi Sethunath; Nebiyou Y Metaferia; Marina F Nogueira; Daniel S Gallant; Emma R Garner; Lauren A Lairson; Christopher M Penney; Jiao Li; Maya K Gelbard; Sarah Abou Alaiwi; Ji-Heui Seo; Justin H Hwang; Craig A Strathdee; Sylvan C Baca; Shatha AbuHammad; Xiaoyang Zhang; John G Doench; William C Hahn; David Y Takeda; Matthew L Freedman; Peter S Choi; Srinivas R Viswanathan

doi:10.1016/j.celrep.2022.110417

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

Cell Rep. 2022 Feb 22;38(8):110417. doi: 10.1016/j.celrep.2022.110417.

Authors

Stephen Tang¹, Vidyalakshmi Sethunath¹, Nebiyou Y Metaferia¹, Marina F Nogueira¹, Daniel S Gallant¹, Emma R Garner¹, Lauren A Lairson², Christopher M Penney², Jiao Li¹, Maya K Gelbard¹, Sarah Abou Alaiwi³, Ji-Heui Seo³, Justin H Hwang⁴, Craig A Strathdee⁵, Sylvan C Baca⁶, Shatha AbuHammad¹, Xiaoyang Zhang⁷, John G Doench⁵, William C Hahn⁸, David Y Takeda⁹, Matthew L Freedman¹⁰, Peter S Choi¹¹, Srinivas R Viswanathan¹²

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA.
⁹ Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
¹¹ Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology & Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: peter.choi@pennmedicine.upenn.edu.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA. Electronic address: srinivas.viswanathan@dfci.harvard.edu.

Abstract

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.

Keywords: CRISPR screen; PRMT1; androgen receptor; prostate cancer; splicing; superenhancer; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Androgen Antagonists / pharmacology
Androgen Antagonists / therapeutic use
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Male
Prostate / metabolism
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms, Castration-Resistant* / genetics
Protein-Arginine N-Methyltransferases / genetics
Protein-Arginine N-Methyltransferases / metabolism
Receptors, Androgen / genetics
Receptors, Androgen / metabolism
Repressor Proteins / metabolism
Signal Transduction

Substances

Androgen Antagonists
Receptors, Androgen
Repressor Proteins
PRMT1 protein, human
Protein-Arginine N-Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding