VARS1 fuels prostate cancer evolution via codon-selective translational rewiring

Cancers exhibit translatomic alterations, but little is known about the drivers that control translational dysregulation and can also be exploited therapeutically in prostate cancer (PCa). By systematic interrogating a group of genes associated with transfer RNA (tRNA) biology (termed as tRNA biogenesis), here we establish tRNA biogenesis as an overall oncogenic pathway in, and identify valyl-tRNA synthetase (VARS1) as the key underlying driver of, PCa progression. Targeting VARS1 reduces the charged levels of valine tRNAs, inhibits global translation and suppresses aggressive PCa both in vitro and in vivo. Surprisingly, knocking down VARS1 does not preferentially impact on translation of valine-rich transcripts, but instead switches the usage of PCa-preferred GTA and GTT codons to GTC and GTC codons, which are optimal in normal prostates. Mechanistically, overexpressed VARS1 in PCa selectively accelerates the translation of genes with high GTA and GTT codon content that are functionally tied to cell mitosis and cancer-promoting pathways. Dietary valine restriction (VR) reduces global translation and slows the growth of both AR+ and AR--xenograft models. We have also developed a VARS1 inhibitor that suppresses autochthonous prostate tumours by targeting its aminoacylation activity. Altogether, our studies indicate that VARS1 acts as an oncogene promoting PCa progression through codon-selective translational rewiring, and therefore represents a therapeutic target susceptible to dietary VR and small molecule therapy.