@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}, 
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 (PDACs). We report widespread, recurrent, and functionally relevant 3′-UTR alterations associated with gene expression changes of known and newly identified PDAC 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 PDAC 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 PDAC patients. Finally, we identify and validate the casein kinase CSNK1A1 (also known as CK1alpha or CK1a) as an APA-regulated therapeutic target in PDAC. Knockdown or pharmacological inhibition of CSNK1A1 attenuates PDAC cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of protumorigenic gene expression in PDAC via the loss of miRNA regulation.}, 
URL = {http://genome.cshlp.org/content/early/2020/03/12/gr.257550.119.abstract}, 
eprint = {http://genome.cshlp.org/content/early/2020/03/12/gr.257550.119.full.pdf+html}, 
journal = {Genome Research} 
}