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
Included in
Bioinformatics Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Medical Cell Biology Commons, Oncology Commons
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Associated Data
PMID: 38849541