Enzymes that modify wobble uridine 34 tRNAs (U34 enzymes) maintain HIF1α levels in BRAFV600E melanoma.

  • Major finding: Enzymes that modify wobble uridine 34 tRNAs (U34 enzymes) maintain HIF1α levels in BRAFV600E melanoma.

  • Concept: U34 enzymes promote glycolysis through direct, codon-dependent regulation of HIF1A translation.

  • Impact: U34 enzyme upregulation in patients with BRAFV600E may be a mechanism of resistance to RAF inhibitors.

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Aberrant mRNA translation can promote tumorigenesis and drug resistance, but the molecular mechanisms have not been fully elucidated. Wobble tRNA modifications are essential for the translation of specific codons, and the enzymes that carry out the modifications of wobble uridine 34 tRNA (U34 enzymes) were shown to be upregulated in BRAFV600E melanoma cells in zebrafish. Rapino and colleagues found that the U34 enzymes ELP1, ELP3, and CTU2 were also upregulated in human melanomas and melanoma cell lines, indicating a potential role for U34 tRNA modification in BRAFV600E melanomagenesis. The HIF1A mRNA sequence is enriched for codons that require U34 tRNA modifications, suggesting that it requires U34 enzymes for accurate translation. Indeed, the U34 enzymes promoted codon-dependent regulation of HIF1A translation, thereby increasing HIF1α levels to promote glycolytic gene expression in BRAFV600E melanoma cells and reducing the dependence on the tricarboxylic acid cycle. Further, HIF1α loss phenocopied U34 enzyme loss of function and reduced the survival of BRAFV600E cells. Patients with BRAFV600E melanoma often respond to RAF inhibitors, but rapidly develop acquired resistance. Analysis of data from The Cancer Genome Atlas revealed that U34 enzymes were upregulated in patients who had acquired resistance to the RAF inhibitor vemurafenib, and increased expression of U34 enzymes was also linked to increased HIF1α levels, suggesting that U34 enzymes may be associated with resistance to RAF inhibitors in patients with BRAFV600E melanoma. Moreover, U34 enzyme depletion resensitized vemurafenib-resistant BRAFV600E cells to RAF inhibition. In vivo, inhibition of ELP3 or CTU2 sensitized resistant melanoma xenografts to vemurafenib. Activation of PI3K signaling, which is one mechanism of resistance to RAF inhibition, increased U34 enzyme levels, elucidating a potential role for U34 enzymes in drug resistance. In addition to demonstrating that U34 enzymes maintain HIF1α levels, these findings suggest a role for U34 enzymes in melanoma progression and drug resistance.

Rapino F, Delaunay S, Rambow F, Zhou Z, Tharun L, De Tullio P, et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 2018;558:605–9.

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