FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell

Sébastien Relier, et al.

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Jan 10, 2020
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Received Date: 19th December 19

Sébastien Relier, Julie Ripoll, Hélène Guillorit, Amandine Amalric, Florence Boissière, Jerome Vialaret, Aurore Attina, Françoise Debart, Armelle Choquet, Françoise Macari1 5 , Emmanuelle Samalin, Jean-Jacques Vasseur, Julie Pannequin, Evelyne 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 dynamic 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 m6Am (N6,2'-O-dimethyladenosine) 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, partially reverses this phenotype. FTO-mediated regulation of m6Am marking constitutes a novel, reversible pathway controlling CSC abilities that does not involve transcriptome remodeling, but could fine-tune translation efficiency of selected m6Am marked transcripts. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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