N6-methyladenosine regulates glycolysis of cancer cells through PDK4

Zihan Li, Yanxi Peng, Jiexin Li, Zhuojia Chen, Feng Chen, Jian Tu, Shuibin Lin and Hongsheng Wang ()
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Zihan Li: Sun Yat-sen University
Yanxi Peng: Sun Yat-sen University
Jiexin Li: Sun Yat-sen University
Zhuojia Chen: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine
Feng Chen: Sun Yat-sen University
Jian Tu: University of South China
Shuibin Lin: Sun Yat-sen University
Hongsheng Wang: Sun Yat-sen University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Studies on biological functions of N6-methyladenosine (m6A) modification in mRNA have sprung up in recent years. We find m6A can positively regulate the glycolysis of cancer cells. Specifically, m6A-sequencing and functional studies confirm that pyruvate dehydrogenase kinase 4 (PDK4) is involved in m6A regulated glycolysis and ATP generation. The m6A 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 m6A by dm6ACRISPR 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 m6A/PDK4 in tumor growth and progression of cervical and liver cancer. Our study reveals that m6A regulates glycolysis of cancer cells through PDK4.

Date: 2020
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DOI: 10.1038/s41467-020-16306-5

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