Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer

Significance Defects in transfer RNA (tRNA) modifications occur in human pathologies such as cancer; however, how these alterations contribute to the disease is poorly understood. One example is the tumor-specific hypomodification of position 37 of tRNA Phe , which was first described 45 y ago, although its cause and consequences have remained unknown. Here we report that the tRNA Phe hypomodification is due to promoter CpG island hypermethylation-associated transcriptional silencing of TYW2, a key enzyme in the synthesis of wybutosine derivatives. Furthermore, epigenetic loss of TYW2 in transformed cells provokes hypomodified tRNA Phe -mediated ribosome frameshifting, dysregulating mRNA abundance via nonsense-mediated decay. Importantly, TYW2 silencing in cancer cells confers enhanced migration and epithelial-to-mesenchymal features that are associated in early-stage colorectal cancer patients with poor clinical outcome.