3'untranslated regions of tumor suppressor genes evolved specific features to favor cancer resistance.

Cancer-related genes have evolved specific genetic and genomic features to favor tumor suppression. Previously we reported that tumor suppressor genes (TSGs) acquired high promoter CpG dinucleotide frequencies during evolution to maintain high expression in normal tissues and resist cancer-specific downregulation. In this study, we investigated whether 3'untranslated regions (3'UTRs) of TSGs have evolved specific features to carry out similar functions. We found that 3'UTRs of TSGs, especially those involved in multiple histological types and pediatric cancers, are longer than those of non-cancer genes. 3'UTRs of TSGs also exhibit higher density of binding sites for RNA-binding proteins (RBPs), particularly those having high affinities to C-rich motifs. Both longer 3'UTR length and RBP binding sites enrichment are correlated with higher gene expression in normal tissues across tissue types. Moreover, both features together with the correlated N6-methyladenosine modification and the extent of protein-protein interactions are positively associated with the ability of TSGs to resist cancer-specific downregulation. These results were successfully validated with independent datasets. Collectively, these findings indicate that TSGs have evolved longer 3'UTR with increased propensity to RBP binding, N6-methyladenosine modification and protein-protein interactions for optimizing their tumor-suppressing functions.