Reference : Codon-specific translation reprogramming promotes resistance to targeted therapy
Scientific journals : Article
Human health sciences : Oncology
http://hdl.handle.net/2268/225765
Codon-specific translation reprogramming promotes resistance to targeted therapy
English
Rapino, Francesca mailto [Université de Liège - ULiège > Département de pharmacie > Chimie médicale >]
Delaunay, Sylvain mailto [Université de Liège > Département de pharmacie > Chimie médicale >]
Rambow, Florian [> >]
Zhou, Zhaoli mailto [Université de Liège > Département de pharmacie > Chimie médicale >]
Tharun, Lars [> >]
De Tullio, Pascal mailto [Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique >]
Sin, Olga [> >]
Shostak, Kateryna mailto [Université de Liège - ULiège > Département de pharmacie > Chimie médicale >]
Schmitz, Sebastian mailto [> >]
Piepers, Jolanda [> >]
Guesquière, Bart [> >]
Karim, Latifa mailto [Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire >]
Charloteaux, Benoît mailto [Université de Liège - ULiège > > GIGA-Research >]
Jamart, Diane mailto [> >]
Florin, Alexandra [> >]
Lambert, Charles mailto [> >]
RORIVE, Andrée mailto [Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'oncologie médicale >]
JERUSALEM, Guy mailto [Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'oncologie médicale >]
Leucci, Eleonora [> >]
Dewaele, Michael [> >]
Vooijs, Marc [> >]
Leidel, Sebastian A [> >]
Georges, Michel mailto [Université de Liège - ULiège > Dpt. de gestion vétérinaire des Ressources Animales (DRA) > GIGA-R : Génomique animale >]
Voz, Marianne mailto [Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire >]
Peers, Bernard mailto [Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire >]
Büttner, Reinhard [> >]
Marine, Jean-Christophe [> >]
Chariot, Alain mailto [Université de Liège - ULiège > Département de pharmacie > Chimie médicale >]
Close, Pierre mailto [Université de Liège - ULiège > Département de pharmacie > Chimie médicale >]
28-Jun-2018
Nature
Nature Publishing Group
558
605-609
Yes (verified by ORBi)
International
0028-0836
1476-4687
United Kingdom
[en] Melanoma ; Cancer ; Targeted therapies
[en] Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation. 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.
GIGA Molecular Biology of Diseases
WELBIO, FNRS, TELEVIE, Fondation belge contre le cancer, ARC, ULiège, Fonds Léon Frédéricq
Researchers ; Professionals ; Students
http://hdl.handle.net/2268/225765
10.1038/s41586-018-0243-7

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