Nat Commun. 2021 Mar 19;12(1):1716
FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell
Sébastien Relier, Julie Ripoll , Hélène Guillorit , Amandine Amalric, Cyrinne Achou , Florence Boissière , Jérôme Vialaret , Aurore Attina , Françoise Debart, Armelle Choquet, Françoise Macari, Virginie Marchand, Yuri Motorin, Emmanuelle Samalin, Jean-Jacques Vasseur, Julie Pannequin, Francesca Aguilo, Evelyne Lopez-Crapez, Christophe Hirtz, Eric Rivals , Amandine Bastide , Alexandre David
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 N6,2′-O-dimethyladenosine (m6Am) demethylase activity. While m6Am is strategically located next to the m7G-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 m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m6Am modification in stem-like properties acquisition. FTO-mediated regulation of m6Am marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.