Codon-specific translation reprogramming promotes resistance to targeted therapy

• Published in: Nature (London) Vol. 558; no. 7711; pp. 605 - 609
• Main Authors: Rapino, Francesca, Delaunay, Sylvain, Rambow, Florian, Zhou, Zhaoli, Tharun, Lars, De Tullio, Pascal, Sin, Olga, Shostak, Kateryna, Schmitz, Sebastian, Piepers, Jolanda, Ghesquière, Bart, Karim, Latifa, Charloteaux, Benoit, Jamart, Diane, Florin, Alexandra, Lambert, Charles, Rorive, Andrée, Jerusalem, Guy, Leucci, Eleonora, Dewaele, Michael, Vooijs, Marc, Leidel, Sebastian A., Georges, Michel, Voz, Marianne, Peers, Bernard, Büttner, Reinhard, Marine, Jean-Christophe, Chariot, Alain, Close, Pierre
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 01.06.2018; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/51; 13/89; 13/95; 49; 49/91; 631/337/574/1793; 631/67/1059/2326; 631/67/1813/1634; 631/80/304; 64; 64/116; 64/60; 82/58; 96/109; Animals; Cancer; Cancer research; Cancer treatment; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Cell Line, Tumor; Cell survival; Chemical compounds; Codon - drug effects; Codon - genetics; Codons; Decoding; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzymes; Female; Gene expression; Genomes; Glucose metabolism; Glycolysis; Human health sciences; Humanities and Social Sciences; Humans; Kinases; Letter; Male; MAP kinase; Mechanistic Target of Rapamycin Complex 2 - metabolism; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Melanoma, Experimental - drug therapy; Melanoma, Experimental - genetics; Melanoma, Experimental - pathology; Messenger RNA; Metabolism; Mice; Mice, Inbred NOD; Mice, SCID; Molecular chains; Molecular modelling; mRNA; multidisciplinary; Mutation; Oncologie; Oncology; Pharmacology; Phosphorylation; Protein biosynthesis; Protein Biosynthesis - drug effects; Protein synthesis; Proteins; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Transfer - chemistry; RNA, Transfer - genetics; RNA, Transfer - metabolism; Science; Sciences de la santé humaine; Short term; Signal Transduction; Signaling; Survival; Targeted therapies; Therapy; Transfer RNA; Transformation; Translation; Translation (Genetics); tRNA; Uridine; Uridine - chemistry; Uridine - genetics; Uridine - metabolism; Vemurafenib - pharmacology; Vemurafenib - therapeutic use; Zebrafish - genetics
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-018-0243-7

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 U 34 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 HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U 34 enzymes and HIF1α. Together, these results demonstrate that U 34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. Enzymes that catalyse modifications of wobble uridine 34 tRNA are essential for the survival of melanoma cells that rely on HIF1α-dependent metabolism through codon-dependent regulation of the translation of HIF1A mRNA.