Rapino, Francesca ORCID: 0000-0002-4343-3805, Delaunay, Sylvain, Rambow, Florian, Zhou, Zhaoli, Tharun, Lars, De Tullio, Pascal, Sin, Olga ORCID: 0000-0002-0976-0570, Shostak, Kateryna, Schmitz, Sebastian, Piepers, Jolanda, Ghesquiere, Bart ORCID: 0000-0003-1547-1705, Karim, Latifa, Charloteaux, Benoit, Jamart, Diane, Florin, Alexandra, Lambert, Charles, Rorive, Andree, Jerusalem, Guy, Leucci, Eleonora ORCID: 0000-0002-2898-748X, Dewaele, Michael, Vooijs, Marc, Leidel, Sebastian A., Georges, Michel, Voz, Marianne, Peers, Bernard, Buettner, Reinhard, Marine, Jean-Christophe ORCID: 0000-0003-2433-9837, Chariot, Alain and Close, Pierre (2018). Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature, 558 (7711). S. 605 - 636. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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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 translation(2,3). Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U-34) tRNA (U-34 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 U-34 enzymes. Mechanistically, U-34 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 HIF1 alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U-34 enzymes and HIF1 alpha. Together, these results demonstrate that U-34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rapino, FrancescaUNSPECIFIEDorcid.org/0000-0002-4343-3805UNSPECIFIED
Delaunay, SylvainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rambow, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, ZhaoliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tharun, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Tullio, PascalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sin, OlgaUNSPECIFIEDorcid.org/0000-0002-0976-0570UNSPECIFIED
Shostak, KaterynaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitz, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piepers, JolandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghesquiere, BartUNSPECIFIEDorcid.org/0000-0003-1547-1705UNSPECIFIED
Karim, LatifaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charloteaux, BenoitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jamart, DianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lambert, CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rorive, AndreeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jerusalem, GuyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leucci, EleonoraUNSPECIFIEDorcid.org/0000-0002-2898-748XUNSPECIFIED
Dewaele, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vooijs, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leidel, Sebastian A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Georges, MichelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voz, MarianneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peers, BernardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marine, Jean-ChristopheUNSPECIFIEDorcid.org/0000-0003-2433-9837UNSPECIFIED
Chariot, AlainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Close, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-182501
DOI: 10.1038/s41586-018-0243-7
Journal or Publication Title: Nature
Volume: 558
Number: 7711
Page Range: S. 605 - 636
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4687
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
IMPROVED SURVIVAL; MELANOMA; CELLS; VEMURAFENIB; INHIBITION; MUTATIONS; KINASEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18250

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