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 VellanoHaoqiang 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, Timothy P. Heffernan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number4626
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma'. Together they form a unique fingerprint.

Cite this