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Publication

Codon-specific translation reprogramming promotes resistance to targeted therapy

Journal Contribution - Journal Article

Reprogramming of mRNA translation has a key role in cancer development and drug resistance (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(2,3). 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 BRAF (V600E) oncogene and by resistance to targeted therapy in melanoma. We show that BRAF (V600E) -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 HIF1alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1alpha. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
Journal: Nature
ISSN: 0028-0836
Issue: 7711
Volume: 558
Pages: 605 - 609
Publication year:2018
BOF-keylabel:yes
IOF-keylabel:yes
BOF-publication weight:10
CSS-citation score:3
Authors:International
Authors from:Government, Higher Education
Accessibility:Closed