Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Commun ; 12(1): 4626, 2021 07 30.
Article in English | MEDLINE | ID: mdl-34330913

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.


Subject(s)
Carcinoma, Pancreatic Ductal/genetics , DNA Damage , Pancreatic Neoplasms/genetics , Protein-Arginine N-Methyltransferases/genetics , RNA/genetics , Repressor Proteins/genetics , Animals , Biocatalysis/drug effects , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/prevention & control , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Enzyme Inhibitors/pharmacology , Female , Humans , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/prevention & control , Protein-Arginine N-Methyltransferases/metabolism , RNA/metabolism , RNA Interference , Repressor Proteins/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays/methods
SELECTION OF CITATIONS
SEARCH DETAIL
...