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

Abstract

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 6 ,2’-O-dimethyladenosine (m 6 A m ) demethylase activity. While m 6 A m is strategically located next to the m 7 G-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 m 6 A m level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m 6 A m methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m 6 A m modification in stem-like properties acquisition. FTO-mediated regulation of m 6 A m marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m 6 A m modification and its potential adverse consequences for colorectal cancer management.

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