The 3′ end of the tale-neglected isoforms in cancer

The evolutionary expansion of 3 ' untranslated regions (3 ' UTRs), along with the incorporation of transposable elements and alternative polyadenylation (APA) sites, has introduced additional layers of gene expression control in eukaryotes. Consequently, 3 ' UTRs regulate the stability, translation, and localization of mRNAs by interacting with RNA-binding proteins and non-coding RNAs, thereby contributing to cell-type-specific and context-dependent gene expression. Mounting evidence highlights the importance of non-coding regions, particularly 3 ' UTRs, in normal physiology and disease states, including cancer. Genomic alterations and driver mutations in coding regions play a well-established role in cancer biology. Advances in long-read sequencing and 3 ' UTR-focused genome-/transcriptome-wide association studies (GWAS/TWAS) improve our understanding of transcriptome complexity and how mRNA isoforms with different 3 '-ends may impact protein functions. This Review explores the regulatory roles of 3 ' UTRs, sources of 3 ' UTR isoform diversity, and implications in cancer, emphasizing the need for further research into their diagnostic and therapeutic potential.Impact statement This review highlights how alternative polyadenylation generates diverse mRNA 3 '-end isoforms in cancer. Isoforms with distinct 3 ' UTRs are differentially regulated by microRNAs and RNA-binding proteins, while intronically polyadenylated isoforms can lead to C-terminally truncated proteins with altered functions.