Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma
- Swati Venkat1,
- Arwen A. Tisdale1,
- Johann R. Schwarz1,
- Abdulrahman A. Alahmari1,
- H. Carlo Maurer2,
- Kenneth P. Olive3,
- Kevin H. Eng4,5 and
- Michael E. Feigin1
- 1Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA;
- 2Klinikum rechts der Isar, II. Medizinische Klinik, Technische Universität München, 81675 Munich, Germany;
- 3Herbert Irving Comprehensive Cancer Center, Department of Medicine, Division of Digestive and Liver Diseases, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA;
- 4Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA;
- 5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.257550.119.
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Freely available online through the Genome Research Open Access option.
- Received September 25, 2019.
- Accepted February 4, 2020.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
