N6-methyladenosine regulates glycolysis of cancer cells through PDK4
Zihan Li, Yanxi Peng, Jiexin Li, Zhuojia Chen, Feng Chen, Jian Tu, Shuibin Lin, Hongsheng Wang
Abstract
Abstract Studies on biological functions of N 6 -methyladenosine (m 6 A) modification in mRNA have sprung up in recent years. We find m 6 A can positively regulate the glycolysis of cancer cells. Specifically, m 6 A-sequencing and functional studies confirm that pyruvate dehydrogenase kinase 4 (PDK4) is involved in m 6 A regulated glycolysis and ATP generation. The m 6 A 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 m 6 A by dm 6 ACRISPR 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 m 6 A/PDK4 in tumor growth and progression of cervical and liver cancer. Our study reveals that m 6 A regulates glycolysis of cancer cells through PDK4.