m6A demethylase FTO stabilizes LINK-A to exert oncogenic roles via MCM3-mediated cell-cycle progression and HIF-1α activation

• Published in: Cell reports (Cambridge) Vol. 42; no. 10; p. 113273
• Main Authors: Nan, Yabing, Liu, Shi, Luo, Qingyu, Wu, Xiaowei, Zhao, Pengfei, Chang, Wan, Zhang, Ruixiang, Li, Yin, Liu, Zhihua
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 31-10-2023; Elsevier
• Subjects: CDK1; cell cycle progression; chemoresistance; CP: Cancer; esophageal squamous cell carcinoma; FTO; glycolysis; HIF-1α; LINK-A; m6A; MCM3; FTO; esophageal squamous cell carcinoma; chemoresistance; CP: Cancer; LINK-A; glycolysis; MCM3; CDK1; m6A; cell cycle progression; HIF-1α
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113273

RNA N6-methyladenosine (m6A) modification is implicated in cancer progression, yet its role in regulating long noncoding RNAs during cancer progression remains unclear. Here, we report that the m6A demethylase fat mass and obesity-associated protein (FTO) stabilizes long intergenic noncoding RNA for kinase activation (LINK-A) to promote cell proliferation and chemoresistance in esophageal squamous cell carcinoma (ESCC). Mechanistically, LINK-A promotes the interaction between minichromosome maintenance complex component 3 (MCM3) and cyclin-dependent kinase 1 (CDK1), increasing MCM3 phosphorylation. This phosphorylation facilitates the loading of the MCM complex onto chromatin, which promotes cell-cycle progression and subsequent cell proliferation. Moreover, LINK-A disrupts the interaction between MCM3 and hypoxia-inducible factor 1α (HIF-1α), abrogating MCM3-mediated HIF-1α transcriptional repression and promoting glycolysis and chemoresistance. These results elucidate the mechanism by which FTO-stabilized LINK-A plays oncogenic roles and identify the FTO/LINK-A/MCM3/HIF-1α axis as a promising therapeutic target for ESCC.
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•FTO demethylates and stabilizes LINK-A in an m6A-dependent manner•LINK-A mediates MCM3 phosphorylation to facilitate cell-cycle progression•LINK-A sequesters HIF-1α from MCM3 to elicit its transcriptional activation•Targeting LINK-A sensitizes ESCC to cytotoxic chemotherapy
Nan et al. reveal that the m6A demethylase FTO stabilizes LINK-A to confer ESCC progression and chemoresistance. LINK-A directly interacts with MCM3, promoting CDK1-mediated MCM3 phosphorylation and subsequent cell-cycle progression, as well as disrupting MCM3-mediated HIF-1α transcriptional suppression to trigger tumor glycolysis.