Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma.

Swati Venkat, Arwen A Tisdale, Johann R Schwarz, Abdulrahman A Alahmari, H Carlo Maurer, Kenneth P Olive, Kevin H Eng, Michael E Feigin

Genome research 2020 Mar

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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. © 2020 Venkat et al.; Published by Cold Spring Harbor Laboratory Press.

Citation

Swati Venkat, Arwen A Tisdale, Johann R Schwarz, Abdulrahman A Alahmari, H Carlo Maurer, Kenneth P Olive, Kevin H Eng, Michael E Feigin. Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma. Genome research. 2020 Mar;30(3):347-360