Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

Autor: Chan JJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Zhang B; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.; KAUST Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia., Chew XH; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Salhi A; Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.; KAUST Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia., Kwok ZH; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, MA, USA., Lim CY; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Desi N; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Subramaniam N; A*STAR Skin Research Labs and Skin Research Institute of Singapore, A*STAR, Immunos, Singapore, Singapore., Siemens A; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; The University of British Columbia, Vancouver, British Columbia, Canada., Kinanti T; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Ong S; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Sanchez-Mejias A; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Integra Therapeutics S.L., Barcelona, Spain., Ly PT; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., An O; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Sundar R; Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore.; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; The N.1 Institute for Health, National University of Singapore, Singapore, Singapore., Fan X; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Wang S; Department of Pathology, National University Health System, Singapore, Singapore., Siew BE; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Lee KC; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore., Chong CS; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore., Lieske B; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore., Cheong WK; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore., Goh Y; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Fam WN; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Ooi MG; Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Koh BTH; Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Iyer SG; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Division of Hepatobiliary & Pancreatic Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore., Ling WH; Program in Clinical and Translational Liver Cancer Research, National Cancer Center Singapore, Singapore, Singapore., Chen J; Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Yoong BK; Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Chanwat R; Hepato-Pancreato-Biliary Surgery Unit, Department of Surgery, National Cancer Institute, Bangkok, Thailand., Bonney GK; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Division of Hepatobiliary & Pancreatic Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore., Goh BKP; Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital and National Cancer Center Singapore, Singapore, Singapore., Zhai W; Program in Clinical and Translational Liver Cancer Research, National Cancer Center Singapore, Singapore, Singapore.; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China., Fullwood MJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Wang W; Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Tan KK; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore., Chng WJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Dan YY; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Pitt JJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Roca X; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Guccione E; Center for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA., Vardy LA; A*STAR Skin Research Labs and Skin Research Institute of Singapore, A*STAR, Immunos, Singapore, Singapore., Chen L; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Gao X; Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.; KAUST Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.; BioMap, Beijing, China., Chow PKH; Program in Clinical and Translational Liver Cancer Research, National Cancer Center Singapore, Singapore, Singapore.; Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital and National Cancer Center Singapore, Singapore, Singapore.; Academic Clinical Programme for Surgery, SingHealth Duke-NUS Academic Medical Centre (AMC), Singapore, Singapore., Yang H; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Tay Y; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. yvonnetay@nus.edu.sg.; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. yvonnetay@nus.edu.sg.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. yvonnetay@nus.edu.sg.
Jazyk: angličtina
Zdroj: Nature cell biology [Nat Cell Biol] 2022 Jun; Vol. 24 (6), pp. 928-939. Date of Electronic Publication: 2022 May 26.
DOI: 10.1038/s41556-022-00913-z
Abstrakt: 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).)
Databáze: MEDLINE
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