Document Type
Article
Publication Date
7-30-2021
Publication Title
Nature Communications
First Page
1
Last Page
19
DOI
https://doi.org/10.1038/s41467-021-24798-y
Additional Publication URL
https://doi.org/10.1038/s41467-021-24798-y
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.
Rights
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The article of record can be found at Nature Communications.
Recommended Citation
Giuliani, Virginia; Miller, Meredith A.; Liu, Chiu-Yi; Hartono, Stella R.; Class, Caleb; Bristow, Christopher A.; Suzuki, Erika; Sanz, Lionel A.; Gao, Guang; Gay, Jason P.; Feng, Ningping; Rose, Johnathon L.; Tomihara, Hideo; Daniele, Joseph R.; Peoples, Michael D.; Bardenhagen, Jennifer P.; Geck Do, Mary K.; Chang, Qing E.; Vangamudi, Bhavatarini; Vellano, Christopher; Ying, Haoqiang; Deem, Angela K.; Do, Kim-Anh; Genovese, Giannicola; Heffernan, Timothy P.; Kovacs, Jeffrey J.; Kim, Michael; Fleming, Jason B.; Guccione, Ernesto; Viale, Andrea; Maitra, Anirban; Di Francesco, M. Emilia; Yap, Timothy A.; Jones, Philip; Draetta, Giulio; Carugo, Alessandro; Chedin, Frederic; and Heffernan, Timothy P., "PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma" (2021). Scholarship and Professional Work – COPHS. 294.
https://digitalcommons.butler.edu/cophs_papers/294
Notes
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The article of record can be found at Nature Communications.