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Conférence CRCT : Dr Alexandre David / IGF, Montpellier – Spatial distribution of FTO adjusts stem-like properties through RNA modification
janvier 13 @ 11:00 - 12:00
Cancer stem cell (CSC) represents a minor subpopulation of tumor cells endowed with self-renewal and multi-lineage differentiation capacity, which can escape from chemotherapies, disseminate and seed metastasis. Understanding the molecular mechanisms that underlie CSC abilities is a major goal to design new therapeutic strategies that may prevent both tumor relapse and metastasis formation. 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 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. We show that low FTO expression in patient-derived cell lines elevates m6Am level in mRNA, which results in enhanced in vivo tumorigenicity and chemoresistance. In the contrary, inhibition of the recently identified m6Am methyltransferase, PCIF1/CAPAM, partially reverses this phenotype. We demonstrate that the FTO/ m6Am axis constitutes a novel, reversible pathway controlling CSC abilities that does not involve transcriptome remodeling, but rather modulates translation efficiency of selected m6Am marked transcripts. Finally, tumor microarrays analysis suggests a compartment-specific role of FTO in colorectal cancer (CRC) initiation and progression. While its expression is strictly nuclear in benign lesions (stage 0), FTO is found in both the nucleus and cytoplasm following malignant transformation (stage 1, 2, 3 and 4). Our latest data suggests that spatial distribution of FTO modulate its accessibility toward relevant substrate and demonstrates that cytoplasmic FTO hampers CSC properties through cap-m6Am demethylation. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for CRC management.