Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, 421001, China.
Nat Commun. 2020 May 22;11(1):2578. doi: 10.1038/s41467-020-16306-5.
Studies on biological functions of N-methyladenosine (mA) modification in mRNA have sprung up in recent years. We find mA can positively regulate the glycolysis of cancer cells. Specifically, mA-sequencing and functional studies confirm that pyruvate dehydrogenase kinase 4 (PDK4) is involved in mA regulated glycolysis and ATP generation. The mA modified 5'UTR of PDK4 positively regulates its translation elongation and mRNA stability via binding with YTHDF1/eEF-2 complex and IGF2BP3, respectively. Targeted specific demethylation of PDK4 mA by dmACRISPR system can significantly decrease the expression of PDK4 and glycolysis of cancer cells. Further, TATA-binding protein (TBP) can transcriptionally increase the expression of Mettl3 in cervical cancer cells via binding to its promoter. In vivo and clinical data confirm the positive roles of mA/PDK4 in tumor growth and progression of cervical and liver cancer. Our study reveals that mA regulates glycolysis of cancer cells through PDK4.
近年来，关于 mRNA 中 N6-甲基腺苷（m6A）修饰的生物学功能的研究如雨后春笋般涌现。我们发现 m6A 可以正向调节癌细胞的糖酵解。具体来说，m6A 测序和功能研究证实，丙酮酸脱氢酶激酶 4（PDK4）参与了 m6A 调控的糖酵解和 ATP 生成。PDK4 的 m6A 修饰的 5'UTR 通过与 YTHDF1/eEF-2 复合物和 IGF2BP3 分别结合，正向调节其翻译延伸和 mRNA 稳定性。通过 dmACRISPR 系统靶向特异性去甲基化 PDK4 的 m6A 可以显著降低癌细胞中 PDK4 的表达和糖酵解。此外，TATA 结合蛋白（TBP）可以通过与其启动子结合，在宫颈癌细胞中转录增加 Mettl3 的表达。体内和临床数据证实了 m6A/PDK4 在宫颈癌和肝癌的肿瘤生长和进展中的积极作用。我们的研究揭示了 m6A 通过 PDK4 调节癌细胞的糖酵解。
