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

Margalida Rosselló-Tortella, Pere Llinàs-Arias, Yuriko Sakaguchi, Kenjyo Miyauchi, Veronica Davalos, Fernando Setien, Maria E. Calleja-Cervantes, David Piñeyro, Jesús Martínez-Gómez, Sonia Guil, Ricky Joshi, Alberto Villanueva (+2 others)
2020 Proceedings of the National Academy of Sciences of the United States of America  
Transfer RNA (tRNA) activity is tightly regulated to provide a physiological protein translation, and tRNA chemical modifications control its function in a complex with ribosomes and messenger RNAs (mRNAs). In this regard, the correct hypermodification of position G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events. Here we report that the tRNA-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional
more » ... d transcriptional silencing in human cancer, particularly in colorectal tumors. The epigenetic loss of TYW2 induces guanosine hypomodification in phenylalanine-tRNA, an increase in −1 ribosome frameshift events, and down-regulation of transcripts by mRNA decay, such as of the key cancer gene ROBO1. Importantly, TYW2 epigenetic inactivation is linked to poor overall survival in patients with early-stage colorectal cancer, a finding that could be related to the observed acquisition of enhanced migration properties and epithelial-to-mesenchymal features in the colon cancer cells that harbor TYW2 DNA methylation-associated loss. These findings provide an illustrative example of how epigenetic changes can modify the epitranscriptome and further support a role for tRNA modifications in cancer biology.
doi:10.1073/pnas.2003358117 pmid:32778592 fatcat:l52myzvjevggdh6464gwuqrjoq