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

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...

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Authors: Rosselló-Tortella, Margalida|||0000-0003-4610-7981, Llinàs-Arias, Pere|||0000-0002-3666-0532, Sakaguchi, Y., Miyauchi, K., Davalos, Veronica|||0000-0003-4077-5137, Setien, Fernando|||0000-0002-4061-4635, Calleja-Cervantes, María Eréndira|||0000-0003-0688-0793, Piñeyro, David|||0000-0001-5633-3339, Martínez-Gómez, Jesús|||0000-0002-7770-073X, Guil, Sonia|||0000-0002-2257-3331, Joshi, Ricky S.|||0000-0003-4463-0453, Villanueva, Alejandro|||0000-0001-5164-0006, Suzuki, Tsutomu, Esteller, M.|||0000-0003-4490-6093
Format: article
Publication Date:2020
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:236595
Online Access:https://ddd.uab.cat/record/236595
https://dx.doi.org/urn:doi:10.1073/pnas.2003358117
Access Level:Open access
Keyword:Cancer
Epigenetics
Transfer RNA
Description
Summary: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.

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