N6-methyladenosine regulates glycolysis of cancer cells through PDK4

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.