PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

Virginia Giuliani (), Meredith A. Miller, Chiu-Yi Liu, Stella R. Hartono, Caleb A. Class, Christopher A. Bristow, Erika Suzuki, Lionel A. Sanz, Guang Gao, Jason P. Gay, Ningping Feng, Johnathon L. Rose, Hideo Tomihara, Joseph R. Daniele, Michael D. Peoples, Jennifer P. Bardenhagen, Mary K. Geck Do, Qing E. Chang, Bhavatarini Vangamudi, Christopher Vellano, Haoqiang Ying, Angela K. Deem, Kim-Anh Do, Giannicola Genovese, Joseph R. Marszalek, Jeffrey J. Kovacs, Michael Kim, Jason B. Fleming, Ernesto Guccione, Andrea Viale, Anirban Maitra, M. Emilia Di Francesco, Timothy A. Yap, Philip Jones, Giulio Draetta, Alessandro Carugo, Frederic Chedin and Timothy P. Heffernan ()
Additional contact information
Virginia Giuliani: Traction, The University of Texas MD Anderson Cancer Center
Meredith A. Miller: Traction, The University of Texas MD Anderson Cancer Center
Chiu-Yi Liu: Traction, The University of Texas MD Anderson Cancer Center
Stella R. Hartono: University of California
Caleb A. Class: The University of Texas MD Anderson Cancer Center
Christopher A. Bristow: Traction, The University of Texas MD Anderson Cancer Center
Erika Suzuki: Traction, The University of Texas MD Anderson Cancer Center
Lionel A. Sanz: University of California
Guang Gao: Traction, The University of Texas MD Anderson Cancer Center
Jason P. Gay: Traction, The University of Texas MD Anderson Cancer Center
Ningping Feng: Traction, The University of Texas MD Anderson Cancer Center
Johnathon L. Rose: The University of Texas MD Anderson Cancer Center
Hideo Tomihara: The University of Texas MD Anderson Cancer Center
Joseph R. Daniele: Traction, The University of Texas MD Anderson Cancer Center
Michael D. Peoples: Traction, The University of Texas MD Anderson Cancer Center
Jennifer P. Bardenhagen: The University of Texas MD Anderson Cancer Center
Mary K. Geck Do: The University of Texas MD Anderson Cancer Center
Qing E. Chang: ORBIT, The University of Texas MD Anderson Cancer Center
Bhavatarini Vangamudi: Traction, The University of Texas MD Anderson Cancer Center
Christopher Vellano: Traction, The University of Texas MD Anderson Cancer Center
Haoqiang Ying: The University of Texas MD Anderson Cancer Center
Angela K. Deem: Traction, The University of Texas MD Anderson Cancer Center
Kim-Anh Do: The University of Texas MD Anderson Cancer Center
Giannicola Genovese: The University of Texas MD Anderson Cancer Center
Joseph R. Marszalek: Traction, The University of Texas MD Anderson Cancer Center
Jeffrey J. Kovacs: Traction, The University of Texas MD Anderson Cancer Center
Michael Kim: The University of Texas MD Anderson Cancer Center
Jason B. Fleming: The University of Texas MD Anderson Cancer Center
Ernesto Guccione: Department of Oncological Sciences and Pharmacological Sciences at Icahn School of Medicine at Mount Sinai
Andrea Viale: The University of Texas MD Anderson Cancer Center
Anirban Maitra: The University of Texas MD Anderson Cancer Center
M. Emilia Di Francesco: The University of Texas MD Anderson Cancer Center
Timothy A. Yap: The University of Texas MD Anderson Cancer Center
Philip Jones: The University of Texas MD Anderson Cancer Center
Giulio Draetta: Traction, The University of Texas MD Anderson Cancer Center
Alessandro Carugo: Traction, The University of Texas MD Anderson Cancer Center
Frederic Chedin: University of California
Timothy P. Heffernan: Traction, The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development. Statement of significance PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.

Date: 2021
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DOI: 10.1038/s41467-021-24798-y

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