Pan-cancer pervasive upregulation of 3 ` UTR splicing drives tumourigenesis
Document Type
Article
Publication Date
6-1-2022
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.
Keywords
Beta-catenin, Rna, Widespread, Elements, Binding, Polyadenylation, Activation, Expression, Complex, 3'-utr
Divisions
surgerydept
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]
Publication Title
Nature Cell Biology
Volume
24
Issue
6
Publisher
Nature Portfolio
Publisher Location
HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY