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TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis

Oncogene volume 35, pages 1785–1796 (2016)Cite this article

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Abstract

Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C α (PKCα) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAiMet), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAiMet. In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAiMet-overexpressing cells, PKCα overexpression decreased tRNAiMet expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAiMet expression with decreased expression of PKCα mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKCα tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.

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Acknowledgements

This work was generously supported by the Institut National du Cancer (INCa) and the Fondation ARC. We thank Martial Seveno, Serge Urbach and Edith Demettre from the 'Plate-forme de Protéomique Fonctionnelle' (FPP) for their work on proteomic analysis of cell samples. We thank the Gustave Roussy Genomic Core Facility (Noemie Pata-Merci) and the Gustave Roussy Bioinformatic Core Facility (Guillaume Meurice). ASB is supported by grants from the Swedish Cancer Foundation (13 0301), Swedish Research Council (621-2012-3576) and Karin and Harald Silvanders Foundation (223-2808-12).

Author information

Author notes

  1. F Macari and Y El-houfi: These authors contributed equally to this work

  2. A David, A Choquet and D Joubert: These authors jointly supervised this work.

Authors and Affiliations

  1. Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France

    F Macari, Y El-houfi, S Khoury-Hanna, J Ollier, L Yazdani, N Legrand, J Pannequin, F Hollande, A David, A Choquet & D Joubert

  2. INSERM, U1191, Montpellier, France

    F Macari, Y El-houfi, S Khoury-Hanna, J Ollier, L Yazdani, N Legrand, J Pannequin, F Hollande, A David, A Choquet & D Joubert

  3. Université de Montpellier, Montpellier, France

    F Macari, Y El-houfi, S Khoury-Hanna, J Ollier, L Yazdani, N Legrand, J Pannequin, F Hollande, A David, A Choquet & D Joubert

  4. Institut Curie, Centre de Recherche, Orsay, France

    G Boldina & S Vagner

  5. CNRS UMR3348, Orsay, France

    G Boldina & S Vagner

  6. University Paris-Sud XI, Orsay, France

    G Boldina & S Vagner

  7. PSL Research University, Paris, France

    G Boldina & S Vagner

  8. Department of Molecular Biology, Umeå University, Umeå, Sweden

    H Xu & A Byström

  9. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA

    G Zheng & T Pan

  10. Laboratory of Oncogenetic, Institut Curie, Hopital René Huguenin, St-Cloud, France

    I Bièche

  11. Laboratoire d’Informatique, de Robotique et de Microélectronique de Montpellier, Montpellier, France

    D Paulet

  12. University of Bordeaux, Institut Européen de Chimie et Biologie, ARNA Laboratory, Pessac, France

    S Durrieu & M Teichmann

  13. Laboratoire de Biologie Cellulaire et Moléculaire, Université Montpellier 1, Montpellier, France

    S Delbecq

  14. USR 3278, CNRS-UPHE-UPVD, CRIOBE, Moorea, French Polynesia

    B Lapeyre

  15. Centre de Recherche de Biochimie Macromoléculaire, CNRS-UMR5237, Montpellier, France

    B Lapeyre

  16. Department of Neurosurgery, Hôpital Gui de Chauliac, Montpellier, France

    L Bauchet

  17. Department of Pathology, Molecular Mechanisms of Tumor Progression Laboratory, University of Melbourne, Melbourne, Victoria, Australia

    F Hollande

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Correspondence to A David or A Choquet.

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Macari, F., El-houfi, Y., Boldina, G. et al. TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis. Oncogene 35, 1785–1796 (2016). https://doi.org/10.1038/onc.2015.244

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