氨酰tRNA合成酶
生物
缬氨酸
转移RNA
黑色素瘤
细胞生物学
核糖核酸
化学
癌症研究
生物化学
氨基酸
基因
作者
Najla El Hachem,Marine Leclercq,Miguel Ruiz,Raphael Vanleyssem,Kateryna Shostak,Pierre-René Körner,Coralie Capron,Lorena Martín-Morales,Patrick Roncarati,Arnaud Lavergne,Arnaud Blomme,Silvia Turchetto,Eric Goffin,Palaniraja Thandapani,Ivan Tarassov,Laurent Nguyen,Bernard Pirotte,Alain Chariot,Jean‐Christophe Marine,Michaël Herfs,Francesca Rapino,Reuven Agami,Pierre Close
标识
DOI:10.1038/s41556-024-01439-2
摘要
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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