4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-021-24798-y

Keywords

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Funding

  1. CPRIT Core Facility Support Grants [RP120348, RP170002]
  2. Flow Cytometry and Cellular Imaging Core Facility (FCCICF) at MDACC
  3. MD Anderson Cancer Center (MDACC) (Cancer Center Support Grant) [CA016672]
  4. MD Anderson Pancreatic Cancer Moon Shots Program
  5. Sheikh Ahmed Center for Pancreatic Cancer Research (Khalifa Foundation)
  6. NIH [R01-GM120607]
  7. CPRIT [RP160471]
  8. DOD [W81XWH-11-1-0418]
  9. Harrington Discovery Institute Grant
  10. Sewell Family Chairmanship in Genomic Medicine

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PRMT1 plays a critical role in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth by regulating RNA metabolism and influencing multiple cellular processes. Inhibition of PRMT1 leads to downregulation of pathways involved in DNA damage response, promoting genomic instability and inhibiting tumor growth.
Arginine methylation by PRMTs is dysregulated in cancer. Here, the authors use functional genomics screens and identify PRMT1 as a vulnerability in pancreatic ductal adenocarcinoma, and further show that PRMT1 regulates RNA metabolism and coordinates expression of genes in cell cycle progression, maintaining genomic stability and tumour growth. 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.

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