Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma
Menée à partir de données de séquençage d'ARN des projets "Genotype-Tissue Expression" et "The Cancer Genome Atlas" portant sur 148 adénocarcinomes canalaires du pancréas, cette étude met en évidence le rôle de la polyadénylation alternative dans l'expression de gènes protumorigènes
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.
Genome Research 2020