Pan-cancer pervasive upregulation of 3′ UTR splicing drives tumourigenesis

Jia Jia Chan, Bin Zhang, Xiao Hong Chew, Adil Salhi, Zhi Hao Kwok, Chun You Lim, Ng Desi, Nagavidya Subramaniam, Angela Siemens, Tyas Kinanti, Shane Ong, Avencia Sanchez-Mejias, Phuong Thao Ly, Omer An, Raghav Sundar, Xiaonan Fan, Shi Wang, Bei En Siew, Kuok Chung Lee, Choon Seng ChongBettina Lieske, Wai-Kit Cheong, Yufen Goh, Wee Nih Fam, Melissa G. Ooi, Bryan T. H. Koh, Shridhar Ganpathi Iyer, Wen Huan Ling, Jianbin Chen, Boon-Koon Yoong, Rawisak Chanwat, Glenn Kunnath Bonney, Brian K. P. Goh, Weiwei Zhai, Melissa J. Fullwood, Wilson Wang, Ker-Kan Tan, Wee Joo Chng, Yock Young Dan, Jason J. Pitt, Xavier Roca, Ernesto Guccione, Leah A. Vardy, Leilei Chen, Xin Gao, Pierce K. H. Chow, Henry Yang, Yvonne Tay

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.
Original languageEnglish (US)
JournalNature Cell Biology
DOIs
StatePublished - May 26 2022

ASJC Scopus subject areas

  • Cell Biology

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