Open AccessEpigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer
Author(s) -
Margalida Rosselló-Tortella,
Pere LlinàsArias,
Yuriko Sakaguchi,
Katsumi Miyauchi,
Verónica Dávalos,
Fernando Setién,
María Eréndira Calleja-Cervantes,
David Piñeyro,
Jesús MartínezGómez,
Sònia Guil,
Ricky S. Joshi,
Alberto Villanueva,
Tsutomu Suzuki,
Manel Esteller
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2003358117
Subject(s) - biology , epigenetics , transfer rna , ribosome , translation (biology) , frameshift mutation , translational frameshift , pseudouridine , genetics , messenger rna , cancer research , rna , microbiology and biotechnology , mutation , gene
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 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.