Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.
Jia Jia ChanBin ZhangXiao Hong ChewAdil SalhiZhi Hao KwokChun You LimNg DesiNagavidya SubramaniamAngela SiemensTyas KinantiShane OngAvencia Sanchez-MejiasPhuong Thao LyOmer AnRaghav SundarXiaonan FanShi WangBei En SiewKuok Chung LeeChoon Seng ChongBettina LieskeWai-Kit CheongYufen GohWee Nih FamMelissa G OoiBryan T H KohShridhar Ganpathi IyerWen Huan LingJianbin ChenBoon-Koon YoongRawisak ChanwatGlenn Kunnath BonneyBrian K P GohWeiwei ZhaiMelissa J FullwoodWilson WangKer-Kan TanWee Joo ChngYock Young DanJason J PittXavier RocaErnesto GuccioneLeah A VardyLeilei ChenXin GaoPierce K H ChowHenry YangYvonne TayPublished in: Nature cell biology (2022)
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.