Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma

Author:

El-Hachem NajlaORCID,Leclercq MarineORCID,Susaeta Ruiz Miguel,Vanleyssem RaphaelORCID,Shostak KaterynaORCID,Körner Pierre-RenéORCID,Capron CoralieORCID,Martin-Morales LorenaORCID,Roncarati Patrick,Lavergne ArnaudORCID,Blomme ArnaudORCID,Turchetto Silvia,Goffin EricORCID,Thandapani Palaniraja,Tarassov IvanORCID,Nguyen LaurentORCID,Pirotte Bernard,Chariot Alain,Marine Jean-Christophe,Herfs MichaelORCID,Rapino FrancescaORCID,Agami ReuvenORCID,Close PierreORCID

Abstract

AbstractTransfer 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.

Publisher

Springer Science and Business Media LLC

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