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An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells

Author

Listed:
  • Shensi Shen

    (Gustave Roussy Cancer Campus)

  • Sara Faouzi

    (Gustave Roussy Cancer Campus
    Université Paris-Sud, Université Paris-Saclay)

  • Amandine Bastide

    (University Montpellier)

  • Sylvain Martineau

    (Institut Curie, PSL Research University, CNRS UMR3348
    Université Paris Sud, Université Paris-Saclay, CNRS UMR3348
    Equipe Labellisée Ligue Nationale Contre le Cancer)

  • Hélène Malka-Mahieu

    (Institut Curie, PSL Research University, CNRS UMR3348
    Université Paris Sud, Université Paris-Saclay, CNRS UMR3348
    Equipe Labellisée Ligue Nationale Contre le Cancer)

  • Yu Fu

    (Gustave Roussy Cancer Campus
    Université Paris-Sud, Université Paris-Saclay)

  • Xiaoxiao Sun

    (University of California)

  • Christine Mateus

    (Gustave Roussy Cancer Campus)

  • Emilie Routier

    (Gustave Roussy Cancer Campus)

  • Severine Roy

    (Gustave Roussy Cancer Campus)

  • Laurent Desaubry

    (CNRS-Strasbourg University)

  • Fabrice André

    (Gustave Roussy Cancer Campus
    Université Paris-Sud, Université Paris-Saclay)

  • Alexander Eggermont

    (Université Paris-Sud, Université Paris-Saclay)

  • Alexandre David

    (University Montpellier)

  • Jean-Yves Scoazec

    (Université Paris-Sud, Université Paris-Saclay)

  • Stéphan Vagner

    (Institut Curie, PSL Research University, CNRS UMR3348
    Université Paris Sud, Université Paris-Saclay, CNRS UMR3348
    Equipe Labellisée Ligue Nationale Contre le Cancer
    Gustave Roussy Cancer Campus)

  • Caroline Robert

    (Gustave Roussy Cancer Campus
    Université Paris-Sud, Université Paris-Saclay
    Gustave Roussy Cancer Campus)

Abstract

Cancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse. Here we show that a subpopulation of BRAFV600 mutant melanoma cells that tolerates exposure to BRAF and MEK inhibitors undergoes a reversible remodelling of mRNA translation that evolves in parallel with drug sensitivity. Although this process is associated with a global reduction in protein synthesis, a subset of mRNAs undergoes an increased efficiency in translation. Inhibiting the eIF4A RNA helicase, a component of the eIF4F translation initiation complex, abrogates this selectively increased translation and is lethal to persister cells. Translation remodelling in persister cells coincides with an increased N6-methyladenosine modification in the 5′-untranslated region of some highly translated mRNAs. Combination of eIF4A inhibitor with BRAF and MEK inhibitors effectively inhibits the emergence of persister cells and may represent a new therapeutic strategy to prevent acquired drug resistance.

Suggested Citation

  • Shensi Shen & Sara Faouzi & Amandine Bastide & Sylvain Martineau & Hélène Malka-Mahieu & Yu Fu & Xiaoxiao Sun & Christine Mateus & Emilie Routier & Severine Roy & Laurent Desaubry & Fabrice André & Al, 2019. "An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13360-6
    DOI: 10.1038/s41467-019-13360-6
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    Cited by:

    1. Lorey K. Smith & Tiffany Parmenter & Margarete Kleinschmidt & Eric P. Kusnadi & Jian Kang & Claire A. Martin & Peter Lau & Riyaben Patel & Julie Lorent & David Papadopoli & Anna Trigos & Teresa Ward &, 2022. "Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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