Abstract
Abstract Tumors can co-opt the mRNA processing machinery to dysregulate the expression of oncogenes and tumor suppressors. One such altered process, termed alternative polyadenylation (APA), is responsible for regulating 3’-untranslated region (UTR) length. APA is driven by a core set of factors that recognize a series of highly conserved sequences within the 3’-UTR on the pre-mRNA. The pre-mRNA is then cleaved before addition of the poly(A) tail. As most transcripts contain several polyadenylation sequences, the choice of where to cleave is a critical determinant of 3’-UTR length. The 3’-UTR contains regulatory sequences, including miRNA binding sites, that control mRNA stability, function, and subcellular localization. Therefore, altering the length of a 3’-UTR can have dramatic impacts on gene function and cellular phenotype. APA factor expression is altered in a variety of cancer types, resulting in dysregulated gene expression. For example, loss of the APA factor CFIm25 in glioblastoma increases cell proliferation through 3’-UTR shortening and upregulated expression of cyclin D1. Pan-cancer analyses have revealed that hundreds of transcripts undergo APA. How these changes in 3’-UTR length are mechanistically linked to changes in gene expression and function are complex and only now being functionally addressed. Despite recent efforts to interrogate APA events in human tumors, numerous critical gaps in knowledge remain. Several pan-cancer analyses have revealed common APA events across diverse tumor types. However, no large-scale, single tumor-type analysis has been reported. Furthermore, the role of APA in pancreatic ductal adenocarcinoma (PDA) has been largely unaddressed. An understanding of the gene-regulatory mechanisms driving PDA progression may provide novel targets for therapeutic intervention. We have performed a comprehensive analysis of differential APA events in normal pancreas and PDA tumors, and observe widespread 3’-UTR shortening in PDA, correlating with expression changes in known PDA drivers and alterations in cancer signaling networks. Experimental validation of candidate genes reveals APA as a novel mechanism of regulation for the PDA oncogene ALDOA, and other genes implicated in pancreatic cancer cell growth, migration, and invasion. Hierarchical clustering of APA events allowed the development of a prognostic signature, identifying patients with poor prognosis. We find that 3’-UTR shortening events drive a preferential loss of tumor suppressive miRNA binding sites, and validate these findings through experimental manipulation of 3’-UTRs in cultured cells. Finally, we identify the serine/threonine kinase casein kinase 1 alpha (CK1) as an APA-regulated, targetable factor driving pancreatic cancer cell growth; inhibition of CK1 attenuates cell proliferation, colony formation, and migration. Our study reveals new mechanisms of dysregulation for cancer promoting genes, highlights the prognostic value of APA analysis, and identifies new targetable factors for PDA. Citation Format: Swati Venkat, Arwen A Tisdale, Kevin H. Eng, Michael E. Feigin. Alternative polyadenylation drives oncogenic gene expression in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A14.
Published Version
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