Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma - Archive ouverte HAL
Article Dans Une Revue Nature Cell Biology Année : 2024

Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma

Najla El-Hachem
Marine Leclercq
Raphael Vanleyssem
Kateryna Shostak
Pierre-René Körner
Coralie Capron
Lorena Martin-Morales
Arnaud Lavergne
Arnaud Blomme
Eric Goffin
Palaniraja Thandapani
  • Fonction : Auteur
Laurent Nguyen
Jean-Christophe Marine
  • Fonction : Auteur
Michael Herfs
Francesca Rapino
Reuven Agami
Pierre Close

Résumé

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.
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Dates et versions

hal-04607080 , version 1 (10-06-2024)

Identifiants

Citer

Najla El-Hachem, Marine Leclercq, Miguel Susaeta Ruiz, Raphael Vanleyssem, Kateryna Shostak, et al.. Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma. Nature Cell Biology, 2024, 26, pp.1154-1164. ⟨10.1038/s41556-024-01439-2⟩. ⟨hal-04607080⟩
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