@article{Venkat06022020,
author = {Venkat, Swati and Tisdale, Arwen A and Schwarz, Johann R and Alahmari, Abdulrahman A and Maurer, H Carlo and Olive, Kenneth P and Eng, Kevin H and Feigin, Michael E}, 
title = {Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma},
year = {2020}, 
doi = {10.1101/gr.257550.119}, 
elocation-id = {gr.257550.119}, 
abstract ={Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3'-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDAs). We report widespread, recurrent and functionally relevant 3'-UTR alterations associated with gene expression changes of known and newly identified PDA growth-promoting genes and experimentally validate the effects of these APA events on protein expression. We find enrichment for APA events in genes associated with known PDA pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3'-UTR forms of metabolic genes. Survival analyses reveal a subset of 3'-UTR alterations that independently characterize a poor prognostic cohort among PDA patients. Finally, we identify and validate the casein kinase CSNK1A1 (also known as CK1alpha or CK1a) as an APA-regulated therapeutic target in PDA. Knockdown or pharmacological inhibition of CSNK1A1 attenuates PDA cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of protumorigenic gene expression in PDA via the loss of miRNA regulation.}, 
URL = {http://genome.cshlp.org/content/early/2020/02/06/gr.257550.119.abstract}, 
eprint = {http://genome.cshlp.org/content/early/2020/02/06/gr.257550.119.full.pdf+html}, 
journal = {Genome Research} 
}