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Author(s): Francesca Rapino [sup.1] [sup.2] , Sylvain Delaunay [sup.1] [sup.2] , Florian Rambow [sup.3] [sup.4] , Zhaoli Zhou [sup.1] [sup.2] , Lars Tharun [sup.5] , Pascal De Tullio [sup.6] , [...], Reprogramming of mRNA translation has a key role in cancer development and drug resistance.sup.1. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation.sup.2,3. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U.sub.34) tRNA (U.sub.34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF.sup.V600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAF.sup.V600E-expressing melanoma cells are dependent on U.sub.34 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 U.sub.34 enzymes. Mechanistically, U.sub.34 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 HIF1[alpha] protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U.sub.34 enzymes and HIF1[alpha]. Together, these results demonstrate that U.sub.34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. Enzymes that catalyse modifications of wobble uridine 34 tRNA are essential for the survival of melanoma cells that rely on HIF1[alpha]-dependent metabolism through codon-dependent regulation of the translation of HIF1A mRNA.

Author(s): Francesca Rapino [sup.1] [sup.2] , Sylvain Delaunay [sup.1] [sup.2] , Florian Rambow [sup.3] [sup.4] , Zhaoli Zhou [sup.1] [sup.2] , Lars Tharun [sup.5] , Pascal De Tullio [sup.6] , [...]