Reprogramming of mRNA translation has a key role in cancer development and drug resistance1. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation2,3. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U34) tRNA (U34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAFV600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAFV600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
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The Tg(mitfa:BRAFV600E);tp53−/− fish were a gift from L. Zon. We thank R. Lo and G. Ghanem for providing short-term melanoma cultures; the CHU Liège patients Biobank facility for technical support and K. Scharmann for technical assistance. We are grateful to the GIGA-zebrafish, imaging, genomics and viral vector facilities for their assistance and the ‘Fonds Leon Fredericq’ and the ‘Centre Anticancéreux’ of the CHU Liège for their financial support. This study was supported by an Incentive Grant for Scientific Research (MIS F:4532.13) from the FNRS, grants from the Concerted Research Action Program (Bio-Acet and tRAME) and Special Research Funds (C-15/44) at the University of Liège, the Belgian foundation against Cancer (FAF-F/2016/840), as well as by the Walloon Excellence in Life Sciences and Biotechnology (WELBIO). F.Rap. was supported by a TELEVIE grant (7.4503.14). S.D., F.Rap., A.C. and P.C. are a research fellow, research assistant, research director and research associate at the FNRS, respectively. J.P. and M. Voo. were supported by a grant from the Dutch Cancer Society (KWF) (UM 2015-2018).