A/Prof. Yvonne TAY Cancer Science Institute Singapore Link to biosketch

Abstract

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) which are important post-transcriptional regulators. In cancer, 3’UTR shortening via alternative polyadenylation can activate oncogenes. However, 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. We find that 3’UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. Targeted inhibition of 3’UTR splicing efficiently reduces oncogene expression and impedes tumor progression.

Notably, we identify CTNNB1 3’UTR splicing as the most consistently dysregulated event across cancers and demonstrate that its spliced 3’UTR variant is the predominant contributor to its oncogenic functions. Overall, our study provides the first compendium of 3’UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.