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.
Highlights
Studies on biological functions of N6-methyladenosine (m6A) modification in mRNA have sprung up in recent years
Our present study reveals that m6A can positively regulate the glycolysis of cancer cells via regulation of pyruvate dehydrogenase kinase 4 (PDK4), one of the most important factors which can direct carbon flux into glycolysis from oxidative phosphorylation (OXPHOS)
Among the 83 glucose metabolism related genes (Supplementary Table 1), we identified the only candidate, pyruvate dehydrogenase kinase 4 (PDK4, Supplementary Table 2), that overlapping among mRNAseq (greater than 2.0-fold variation (p < 0.05) between wild type and Mettl3Mut/- HeLa cells, Supplementary Data 1) and m6A sequencing (m6A-seq) (Fig. 2c)
Summary
Studies on biological functions of N6-methyladenosine (m6A) modification in mRNA have sprung up in recent years. 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. Our study reveals that m6A regulates glycolysis of cancer cells through PDK4. M6A can regulate the splicing, translation, and decay rates of mRNA to affect protein production and various biological processes such as cell differentiation, embryonic development, and stress responses[7]. The roles of m6A modification in regulating mRNA processing of metabolic-related genes and affecting metabolism of cancer cells remain unknown. Our present study reveals that m6A can positively regulate the glycolysis of cancer cells via regulation of pyruvate dehydrogenase kinase 4 (PDK4), one of the most important factors which can direct carbon flux into glycolysis from oxidative phosphorylation (OXPHOS). The methylation of 5′UTR of PDK4 can regulate the mRNA stability and translation of PDK4 via recruitment of different reader proteins
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