Abstract RNA N 6 -methyladenosine (m 6 A) modification, balanced by methyltransferases and demethylases, has recently been shown to play critical roles in multiple cancers. However, the mechanism by which m 6 A modification regulates long noncoding RNA (lncRNA) stability and function during cancer progression remains unclear. Here, we show that m 6 A demethylase fat mass and obesity-associated protein (FTO) removes the m 6 A 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 1α (HIF-1α), abrogates MCM3-mediated transcriptional repression of HIF-1α, 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-1α axis as a promising therapeutic target for ESCC.

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