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

Chan, Jia Jia and Zhang, Bin and Chew, Xiao Hong and Salhi, Adil and Kwok, Zhi Hao and Lim, Chun You and Desi, Ng and Subramaniam, Nagavidya and Siemens, Angela and Kinanti, Tyas and Ong, Shane and Sanchez-Mejias, Avencia and Ly, Phuong Thao and An, Omer and Sundar, Raghav and Fan, Xiaonan and Wang, Shi and Siew, Bei En and Lee, Kuok Chung and Chong, Choon Seng and Lieske, Bettina and Cheong, Wai-Kit and Goh, Yufen and Fam, Wee Nih and Ooi, Melissa G. and Koh, Bryan T. H. and Iyer, Shridhar Ganpathi and Ling, Wen Huan and Chen, Jianbin and Yoong, Boon-Koon and Chanwat, Rawisak and Bonney, Glenn Kunnath and Goh, Brian K. P. and Zhai, Weiwei and Fullwood, Melissa J. and Wang, Wilson and Tan, Ker-Kan and Chng, Wee Joo and Dan, Yock Young and Pitt, Jason J. and Roca, Xavier and Guccione, Ernesto and Vardy, Leah A. and Chen, Leilei and Gao, Xin and Chow, Pierce K. H. and Yang, Henry and Tay, Yvonne (2022) Pan-cancer pervasive upregulation of 3 ` UTR splicing drives tumourigenesis. Nature Cell Biology, 24 (6). 928+. ISSN 1465-7392, DOI

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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 ( 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.

Item Type: Article
Funders: NMRC OF-IRGs [Grant No; NMRC/OFIRG/MOH-000380, MOH000923], National Research Foundation, Singapore, Ministry of Education, Singapore, RNA Biology Center at the Cancer Science Institute of Singapore, Ministry of Education, Singapore [Grant No; MOE2014-T3-1-006], National Medical Research Council, Singapore [Grant No; TCR/015-NCC/2016, NMRC/CSA-SI/0018/2017], P.K.H.C. King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) [Grant No; BAS/1/1624-01, FCC/1/1976-2301, FCC/1/1976-26-01, REI/1/0018-01-01, REI/1/4216-01-01, REI/1/4437-01-01, REI/1/4473-01-01, URF/1/4098-01-01]
Uncontrolled Keywords: Beta-catenin; Rna; Widespread; Elements; Binding; Polyadenylation; Activation; Expression; Complex; 3'-utr
Subjects: R Medicine > RD Surgery
Divisions: Faculty of Medicine > Surgery Department
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 19 Oct 2023 03:18
Last Modified: 19 Oct 2023 03:18

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