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

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, Alexander Eggermont, Alexandre David, Jean Yves Scoazec, Stéphan Vagner, Caroline Robert

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

36 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Artikelnummer5713
TijdschriftNature Communications
Volume10
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 1 dec. 2019
Extern gepubliceerdJa

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