Faculty, Staff and Student Publications
Publication Date
7-1-2024
Journal
Nature Cell Biology
Abstract
Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.
Keywords
Animals, Humans, Mice, Amino Acyl-tRNA Synthetases, Cell Line, Tumor, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Melanoma, Protein Biosynthesis, Protein Kinase Inhibitors, Valine, Xenograft Model Antitumor Assays
DOI
10.1038/s41556-024-01439-2
PMID
38849541
PMCID
PMC11252002
PubMedCentral® Posted Date
June 2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
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Bioinformatics Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Medical Cell Biology Commons, Oncology Commons
