Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Transfer RNA (tRNA) dynamics influence cancer development by regulating codon-specific messenger RNA (mRNA) translation.
• Aminoacyl-tRNA synthetases (aaRSs) play dual roles in cancer, potentially promoting or suppressing tumorigenesis.

Purpose of the Study:

• To investigate the role of valine aminoacyl-tRNA synthetase (VARS) in MAPK therapy resistance in melanoma.
• To elucidate the mechanism by which VARS contributes to acquired resistance and identify potential therapeutic targets.

Main Methods:

• Analysis of proteome rewiring in patient-derived MAPK therapy-resistant melanoma.
• Assessment of valine tRNA and VARS expression and activity in resistant melanoma.
• VARS knockdown experiments in vitro and in vivo.
• Investigation of VARS-regulated mRNA translation, focusing on valine-enriched transcripts.

Main Results:

• MAPK therapy resistance in melanoma is associated with codon-biased translation favoring valine, increased valine tRNA levels, and upregulated VARS.
• VARS knockdown resensitizes MAPK-resistant melanoma cells and tumors to therapy.
• VARS regulates the translation of valine-enriched transcripts, including hydroxyacyl-CoA dehydrogenase mRNA, crucial for fatty acid oxidation.
• Resistant melanoma cells depend on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for survival under MAPK treatment.

Conclusions:

• VARS is a critical mediator of codon-biased translation reprogramming in MAPK therapy-resistant melanoma.
• Targeting VARS can overcome acquired resistance to MAPK-targeted therapy in melanoma.
• VARS represents a promising therapeutic target for treating therapy-resistant melanoma.