Pan-cancer pervasive upregulation of 3′ UTR splicing drives tumourigenesis
AuthorsChan, Jia Jia
Chew, Xiao Hong
Kwok, Zhi Hao
Lim, Chun You
Ly, Phuong Thao
Siew, Bei En
Lee, Kuok Chung
Chong, Choon Seng
Fam, Wee Nih
Ooi, Melissa G.
Koh, Bryan T. H.
Iyer, Shridhar Ganpathi
Ling, Wen Huan
Bonney, Glenn Kunnath
Goh, Brian K. P.
Fullwood, Melissa J.
Chng, Wee Joo
Dan, Yock Young
Pitt, Jason J.
Vardy, Leah A.
Chow, Pierce K. H.
KAUST DepartmentComputational Bioscience Research Center (CBRC)
Computer Science Program
Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
Computer, Electrical and Mathematical Science and Engineering (CEMSE) Division
Structural and Functional Bioinformatics Group
KAUST Grant NumberBAS/1/1624-01
Permanent link to this recordhttp://hdl.handle.net/10754/678270
MetadataShow full item record
AbstractMost 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.
CitationChan, J. J., Zhang, B., Chew, X. H., Salhi, A., Kwok, Z. H., Lim, C. Y., Desi, N., Subramaniam, N., Siemens, A., Kinanti, T., Ong, S., Sanchez-Mejias, A., Ly, P. T., An, O., Sundar, R., Fan, X., Wang, S., Siew, B. E., Lee, K. C., … Tay, Y. (2022). Pan-cancer pervasive upregulation of 3′ UTR splicing drives tumourigenesis. Nature Cell Biology. https://doi.org/10.1038/s41556-022-00913-z
SponsorsWe thank all past and present Y.T. lab members for their constructive feedback on this project, V. Teh for providing the mouse RNA samples, the NUHS Leukemia Cell Bank for the AML samples and S. J. Tang for help with ASO design. The computational analysis in this study is supported by National Supercomputing Centre Singapore (NSCC). Y.T. is funded by NMRC OF-IRGs (NMRC/OFIRG/MOH-000380, MOH-000923), the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, and the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s AcRF Tier 3 grants (MOE2014-T3-1-006). Singapore National Medical Research Council grants (TCR/015-NCC/2016 and NMRC/CSA-SI/0018/2017): P.K.H.C. King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) (BAS/1/1624-01, FCC/1/1976-23-01, 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 and URF/1/4098-01-01): X.G.
PublisherSpringer Science and Business Media LLC
JournalNature Cell Biology
Except where otherwise noted, this item's license is described as Archived with thanks to Nature Cell Biology under a Creative Commons license, details at: https://creativecommons.org/licenses/by/4.0
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