Enzymes That Catalyze Wobble tRNA Modification Promote Melanomagenesis

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 BRAF^V600E 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 BRAF^V600E 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 BRAF^V600E 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 BRAF^V600E cells. Patients with BRAF^V600E 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 BRAF^V600E melanoma. Moreover, U₃₄ enzyme depletion resensitized vemurafenib-resistant BRAF^V600E 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.

• ©2018 American Association for Cancer Research.