Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma.

[en] 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.

Disciplines :

Oncology

Author, co-author :

El Hachem, Najla ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling

Leclercq, Marine ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling

Susaeta Ruiz, Miguel ; Université de Liège - ULiège > GIGA

Vanleyssem, Raphaël ; Université de Liège - ULiège > Département de pharmacie

Shostak, Kateryna ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Körner, Pierre-René ; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Capron, Coralie ; Université de Liège - ULiège > GIGA

Martin Morales, Lorena ; Université de Liège - ULiège > Département de pharmacie

RONCARATI, Patrick ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques

Lavergne, Arnaud ; Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA) > Génomique animale

More authors (13 more)

Language :

English

Title :

Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma.

Publication date :

07 June 2024

Journal title :

Nature Cell Biology

ISSN :

1465-7392

eISSN :

1476-4679

Publisher :

Springer Science and Business Media LLC, England

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.nature.com/articles/s41556-024-01439-2.pdf

Available on ORBi :

since 11 July 2024

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