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

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.