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

We identified that the m6A demethylase FTO demethylates and stabilizes a lncRNA long intergenic noncoding RNA for kinase activation (LINK-A) during ESCC chemoresistance. LINK-A directly interacts with minichromosome maintenance complex component 3 (MCM3) and increases the phosphorylation of MCM3 at Ser112 by cyclin-dependent kinase 1 (CDK1), which facilitates MCM3 incorporation into the MCM2-7 complex and subsequent chromatin loading, promoting cell cycle progression. On the other hand, LINK-A insulates the interaction between MCM3 and HIF-1α to free HIF-1α. The enhancement of HIF-1α transcriptional activity reprograms metabolic status from OXPHOS to glycolysis. Additionally, targeting LINK-A substantially sensitized ESCC patient-derived xenografts (PDXs) to first-line chemotherapy, thus indicating LINK-A is a promising target for cancer treatment. RNA-seq of LINK-A knockdown (SH2, SH4) and control (SHC) KYSE450 cells