Most mammalian genes generate messenger RNAs (mRNAs) that consist of central protein-coding regions flanked by variable untranslated regions (UTRs). These UTRs, while not directly involved in protein production, nevertheless harbour many regulatory sequences and structures, and play important roles in post-transcriptional regulation, ensuring correct gene expression and function. Changes to these UTRs can be pathogenic, as seen in the case of shortened 3’ UTR ends via alternative polyadenylation triggering oncogenesis. UTR splicing remains poorly understood however, as while alternative splicing to increase transcriptome and proteome diversity is well-characterised in most mammalian genes, research heretofore has overwhelmingly concentrated on the protein-coding regions of mRNAs.
To fill this lacuna, a group of researchers led by Dr Yvonne Tay, Principal Investigator at CSI Singapore and President’s Assistant Professor at the Department of Biochemistry, NUS, set out to systematically and comprehensively map out the pan-cancer landscape of 3’UTR splicing. Their results were published in the journal Nature Cell Biology on 26 May 2022, and presented in SpUR (http://www.cbrc.kaust.edu.sa/spur/home/).
In this study, the researchers mapped out the 3’UTR splicing events in 11 cancer types. They found that 3’UTR splicing is widespread, upregulated in cancers, associated with poor clinical outcome and more prevalent in oncogenes. Importantly, they found that CTNNB1 3’UTR splicing is the most consistently dysregulated event across cancer types. They confirmed its upregulation in liver and colon cancer, and demonstrated that said upregulation is a key contributor to tumour formation. They also found that targeted inhibition of 3’UTR splicing efficiently reduces oncogene expression and slows tumour growth.
The results of this study not only highlight the significance of 3’UTR splicing in cancer, but may also form the basis of new RNA-based anti-cancer therapeutics. CTNNB1, a key cancer driver gene, encodes a protein called beta-catenin, which, as a lynchpin protein in multiple cancer signalling pathways, has been a popular target for therapeutic drug companies – but with limited success. The team’s findings could lay the foundation for therapies directly targeted at cancer-associated RNA changes, which may be a potential game changer for genes that are difficult to target at the protein level.
In the future, the team intends to further examine the causes and mechanisms of 3’UTR splicing, as well as expand their studies into other cancer types to identify tissue-specific changes that may be useful predictive markers or therapeutic targets.
Read more here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9203280/