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bioRxiv · 10.1101/2023.01.28.526069

m6A Demethylase FTO Stabilizes LINK-A to Exert Oncogenic Roles via MCM3-Mediated Cell Cycle Progression and HIF-1α Activation

Nan, Y.·Liu, S.·Luo, Q.·Wu, X.·Zhao, P.·Chang, W.·Liu, Z.
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Abstract

RNA N6-methyladenosine (m6A) modification, balanced by methyltransferases and demethylases, has recently been shown to play critical roles in multiple cancers. However, the mechanism by which m6A modification regulates long noncoding RNA (lncRNA) stability and function during cancer progression remains unclear. Here, we show that m6A demethylase fat mass and obesity-associated protein (FTO) removes the m6A modification on long intergenic noncoding RNA for kinase activation (LINK-A) and stabilizes it to promote cell proliferation and cytotoxic chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Mechanistically, LINK-A enhances the interaction between minichromosome maintenance complex component 3 (MCM3) and cyclin-dependent kinase 1 (CDK1) to promote MCM3 phosphorylation by CDK1. MCM3 is a subunit of the hexameric protein complex and its phosphorylation facilitates loading of the MCM complex onto chromatin, which promotes cell cycle progression and subsequent cell proliferation. Meanwhile, LINK-A prevents the interaction of MCM3 and hypoxia-inducible factor 1 (HIF-1), abrogates MCM3-mediated transcriptional repression of HIF-1, and promotes glycolysis and chemoresistance of cancer cells. These results elucidate a mechanism whereby FTO-stabilized LINK-A plays oncogenic roles and present the FTO/LINK-A/MCM3/HIF-1 axis as a promising therapeutic target for ESCC.

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Nan, Y., Liu, S., Luo, Q., Wu, X., Zhao, P., Chang, W., Liu, Z.. 2023-01-30. m6A Demethylase FTO Stabilizes LINK-A to Exert Oncogenic Roles via MCM3-Mediated Cell Cycle Progression and HIF-1α Activation. https://doi.org/10.1101/2023.01.28.526069

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