FTO-mediated cytoplasmic mA demethylation adjusts stem-like properties in colorectal cancer cell.
Fiche publication
Date publication
mars 2021
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MOTORINE Iouri, Dr MARCHAND Virginie
Tous les auteurs :
Relier S, Ripoll J, Guillorit H, Amalric A, Achour C, Boissière F, Vialaret J, Attina A, Debart F, Choquet A, Macari F, Marchand V, Motorin Y, Samalin E, Vasseur JJ, Pannequin J, Aguilo F, Lopez-Crapez E, Hirtz C, Rivals E, Bastide A, David A
Lien Pubmed
Résumé
Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N,2'-O-dimethyladenosine (mA) demethylase activity. While mA is strategically located next to the mG-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates mA level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear mA methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of mA modification in stem-like properties acquisition. FTO-mediated regulation of mA marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the mA modification and its potential adverse consequences for colorectal cancer management.
Référence
Nat Commun. 2021 Mar 19;12(1):1716