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The enzymes catalysing the modification of the wobble uridine (U34) of tRNAs (U34-enzymes) play an important role in tumor development. We have recently demonstrated that the U34-enzymes are crucial in the survival of glycolytic melanoma cultures through a codon-specific regulation of HIF1α mRNA translation. Moreover, depletion of U34-enzymes resensitizes resistant melanoma to targeted therapy. These results indicate that targeting U34-enzymes represents a new therapeutic opportunity for melanoma patients.