Codon-specific translation reprogramming promotes resistance to targeted therapy

Francesca Rapino, Sylvain Delaunay, Florian Rambow, Zhaoli Zhou, Lars Tharun, Pascal Tullio, Olga Sin, Kateryna Shostak, Sebastian Schmitz, Jolanda Piepers, Bart Ghesquière, Latifa Karim, Benoit Charloteaux, Diane Jamart, Alexandra Florin, Charles Lambert, Andrée Rorive, Guy Jerusalem, Eleonora Leucci, Michael Dewaele, Marc Vooijs, Sebastian A. Leidel, Michel Georges, Marianne Voz, Bernard Peers, Reinhard Büttner, Jean-Christophe Marine, Alain Chariot and Pierre Close ()
Additional contact information
Francesca Rapino: University of Liège
Sylvain Delaunay: University of Liège
Florian Rambow: KU Leuven
Zhaoli Zhou: University of Liège
Lars Tharun: University Hospital Cologne
Pascal Tullio: University of Liège
Olga Sin: Max Planck Institute for Molecular Biomedicine
Kateryna Shostak: GIGA-institute, University of Liège
Sebastian Schmitz: University of Liège
Jolanda Piepers: Maastricht University
Bart Ghesquière: VIB
Latifa Karim: GIGA-institute, University of Liège
Benoit Charloteaux: GIGA-institute, University of Liège
Diane Jamart: University of Liège
Alexandra Florin: University Hospital Cologne
Charles Lambert: GIGA-institute, University of Liège
Andrée Rorive: University of Liège
Guy Jerusalem: University of Liège
Eleonora Leucci: KU Leuven
Michael Dewaele: KU Leuven
Marc Vooijs: Maastricht University
Sebastian A. Leidel: Max Planck Institute for Molecular Biomedicine
Michel Georges: GIGA-institute, University of Liège
Marianne Voz: GIGA-institute, University of Liège
Bernard Peers: GIGA-institute, University of Liège
Reinhard Büttner: University Hospital Cologne
Jean-Christophe Marine: KU Leuven
Alain Chariot: GIGA-institute, University of Liège
Pierre Close: University of Liège

Nature, 2018, vol. 558, issue 7711, 605-609

Abstract: Abstract Reprogramming of mRNA translation has a key role in cancer development and drug resistance1. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation2,3. 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 BRAFV600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAFV600E-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 HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.

Date: 2018
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DOI: 10.1038/s41586-018-0243-7

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