RRC ID 67281
Author Giuliani V, Miller MA, Liu CY, Hartono SR, Class CA, Bristow CA, Suzuki E, Sanz LA, Gao G, Gay JP, Feng N, Rose JL, Tomihara H, Daniele JR, Peoples MD, Bardenhagen JP, Geck Do MK, Chang QE, Vangamudi B, Vellano C, Ying H, Deem AK, Do KA, Genovese G, Marszalek JR, Kovacs JJ, Kim M, Fleming JB, Guccione E, Viale A, Maitra A, Emilia Di Francesco M, Yap TA, Jones P, Draetta G, Carugo A, Chedin F, Heffernan TP.
Title PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma.
Journal Nat Commun
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 significancePDAC 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.
Volume 12(1)
Pages 4626
Published 2021-7-30
DOI 10.1038/s41467-021-24798-y
PII 10.1038/s41467-021-24798-y
PMID 34330913
PMC PMC8324870
MeSH Animals Biocatalysis / drug effects Carcinoma, Pancreatic Ductal / genetics* Carcinoma, Pancreatic Ductal / metabolism Carcinoma, Pancreatic Ductal / prevention & control Cell Line, Tumor Cell Proliferation / drug effects Cell Proliferation / genetics DNA Damage* Enzyme Inhibitors / pharmacology Female Humans Mice, Inbred NOD Mice, Knockout Mice, SCID Pancreatic Neoplasms / genetics* Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / prevention & control Protein-Arginine N-Methyltransferases / genetics* Protein-Arginine N-Methyltransferases / metabolism RNA / genetics* RNA / metabolism RNA Interference Repressor Proteins / genetics* Repressor Proteins / metabolism Tumor Burden / drug effects Xenograft Model Antitumor Assays / methods
IF 12.121
Human and Animal Cells PK-59(RCB1901)