Codon-specific translation reprogramming promotes resistance to targeted therapy
Authors: Marianne Voz
Sylvain Delaunay
Jolanda Piepers
Bart Ghesquière
Bernard Peers
Pascal De Tullio
Florian Rambow
Alain Chariot
Sebastian Schmitz
Latifa Karim
Andrée Rorive
Pierre Close
Francesca Rapino
Kateryna Shostak
Lars Tharun
Michael Dewaele
Eleonora Leucci
Michel Georges
Benoit Charloteaux
Sebastian A Leidel
Olga Sin
Reinhard Büttner
Marc Vooijs
Charles Lambert
Zhaoli Zhou
Diane Jamart
Jean-Christophe Marine
Alexandra Florin
Guy Jerusalem
Journal: Nature (2018)
Discipline: Multidisciplinary
Keywords: mRNA translation; cancer development; drug resistance; Wobble tRNA modifications; U34 enzymes
Affiliations: Laboratory of Cancer Signaling, University of Liège, Liège, Belgium., GIGA-institute, University of Liège, Liège, Belgium., Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Center for Cancer Biology, VIB, Leuven, Belgium., Institute for Pathology, University Hospital Cologne, Cologne, Germany., Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium., Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany., Faculty of Medicine, University of Münster, Münster, Germany., Cells-in-Motion Cluster of Excellence, University of Münster, Münster, Germany., Laboratory of Medical Chemistry, University of Liège, Liège, Belgium., Department of Radiotherapy (MAASTRO)/GROW, School for Developmental Biology and Oncology, Maastricht University, Maastricht, The Netherlands., Metabolomics Core Facility, Center for Cancer Biology, VIB, Leuven, Belgium., Unit of Animal Genomics, University of Liège, Liège, Belgium., Medical Oncology, CHU Sart Tilman Liège, University of Liège, Liège, Belgium., WELBIO, University of Liège, Liège, Belgium., Laboratory of Cancer Signaling, University of Liège, Liège, Belgium. ., GIGA-institute, University of Liège, Liège, Belgium. ., WELBIO, University of Liège, Liège, Belgium. .

Abstract:  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 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 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 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. 

Retracted: No

PubPeer comments:
 Questions comments regarding some of the Western immunoblots presented in this article: Why are so many of the Western immunoblots lacking background signal (noise)? E.g. Figure 4B, 5B and 7A. In many of the Western immunoblots, the blots of the total and phosphorylated proteins are very different in appearance (band size and shape). E.g. Figure 5B (p-GSK3beta vs GSK3beta), Figure 5A (p-mTOR vs mTOR) and Figure 7A (p-Akt vs Akt). This shows that they have not been run on the same gel and make it difficult to compare. ![file] ![file] ![file] ,