1. Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.
- Author
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Chan JJ, Zhang B, Chew XH, Salhi A, Kwok ZH, Lim CY, Desi N, Subramaniam N, Siemens A, Kinanti T, Ong S, Sanchez-Mejias A, Ly PT, An O, Sundar R, Fan X, Wang S, Siew BE, Lee KC, Chong CS, Lieske B, Cheong WK, Goh Y, Fam WN, Ooi MG, Koh BTH, Iyer SG, Ling WH, Chen J, Yoong BK, Chanwat R, Bonney GK, Goh BKP, Zhai W, Fullwood MJ, Wang W, Tan KK, Chng WJ, Dan YY, Pitt JJ, Roca X, Guccione E, Vardy LA, Chen L, Gao X, Chow PKH, Yang H, and Tay Y
- Subjects
- 3' Untranslated Regions genetics, Alternative Splicing genetics, Animals, Carcinogenesis genetics, Mammals, Up-Regulation, Adenocarcinoma genetics, Colonic Neoplasms genetics
- Abstract
Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics., (© 2022. The Author(s).)
- Published
- 2022
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