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.
Dioken et al. (Tue,) studied this question.