N ⁶ -methyladenosine regulates glycolysis of cancer cells through PDK4

Abstract

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

Abstract

Dysregulation of N6-Methyladenosine (m ⁶A) is associated with cancer progression. Here, authors show that m ⁶A methylation of pyruvate dehydrogenase kinase 4 (PDK4) positively regulates its mRNA stability and translation, and consequently affects glycolysis in cancer cells