TY  - JOUR
A1  - Venkat, Swati
A1  - Tisdale, Arwen A
A1  - Schwarz, Johann R
A1  - Alahmari, Abdulrahman A
A1  - Maurer, H Carlo
A1  - Olive, Kenneth P
A1  - Eng, Kevin H
A1  - Feigin, Michael E
T1  - Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma
Y1  - 2020/02/06 
JF  - Genome Research 
JO  - Genome Research 
DO  - 10.1101/gr.257550.119 
SP  - gr.257550.119 
UR  - http://genome.cshlp.org/content/early/2020/02/06/gr.257550.119.abstract 
N2  - 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. 
ER  -