FTO-mediated cytoplasmic m 6 A m demethylation adjusts stem-like properties in colorectal cancer cell
FTO-mediated cytoplasmic m 6 A m 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 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.
David Alexandre、Guillorit H¨|l¨¨ne、Boissi¨¨re Florence、Macari Fran?oise、Hirtz Christophe、Bastide Amandine、Samalin Emmanuelle、Rivals Eric、Crapez Evelyne、Relier S¨|bastien、Amalric Amandine、Pannequin Julie、Attina Aurore、Ripoll Julie、Vialaret J¨|r?me、Choquet Armelle、Vasseur Jean-Jacques、Debart Fran?oise
IGF, Univ. Montpellier, CNRS, INSERMIGF, Univ. Montpellier, CNRS, INSERM||AMABIOTICS SASICMIGF, Univ. Montpellier, CNRS, INSERMIRMB, Univ Montpellier, INSERM, CHU Montpellier, CNRSIGF, Univ. Montpellier, CNRS, INSERMIGF, Univ. Montpellier, CNRS, INSERM||ICMLIRMM, Univ. Montpellier, CNRS||Institut de Biologie Computationnelle (IBC), Universit¨| de MontpellierICMIGF, Univ. Montpellier, CNRS, INSERMIGF, Univ. Montpellier, CNRS, INSERMIGF, Univ. Montpellier, CNRS, INSERMIRMB, Univ Montpellier, INSERM, CHU Montpellier, CNRSLIRMM, Univ. Montpellier, CNRS||Institut de Biologie Computationnelle (IBC), Universit¨| de MontpellierIRMB, Univ Montpellier, INSERM, CHU Montpellier, CNRSIGF, Univ. Montpellier, CNRS, INSERMIBMM, CNRS, University Montpellier, ENSCMIBMM, CNRS, University Montpellier, ENSCM
肿瘤学基础医学分子生物学
David Alexandre,Guillorit H¨|l¨¨ne,Boissi¨¨re Florence,Macari Fran?oise,Hirtz Christophe,Bastide Amandine,Samalin Emmanuelle,Rivals Eric,Crapez Evelyne,Relier S¨|bastien,Amalric Amandine,Pannequin Julie,Attina Aurore,Ripoll Julie,Vialaret J¨|r?me,Choquet Armelle,Vasseur Jean-Jacques,Debart Fran?oise.FTO-mediated cytoplasmic m 6 A m demethylation adjusts stem-like properties in colorectal cancer cell[EB/OL].(2025-03-28)[2025-05-23].https://www.biorxiv.org/content/10.1101/2020.01.09.899724.点此复制
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