N 6 -methyladenosine regulates glycolysis of cancer cells through PDK4

• Published in: Nature communications Vol. 11; no. 1; pp. 2578 - 16
• Main Authors: Li, Zihan, Peng, Yanxi, Li, Jiexin, Chen, Zhuojia, Chen, Feng, Tu, Jian, Lin, Shuibin, Wang, Hongsheng
• Format: Journal Article
• Language: English
• Published: England Nature Portfolio 22.05.2020
• Subjects: 5' Untranslated Regions; Adenosine - analogs & derivatives; Adenosine - metabolism; Adenosine Triphosphate - metabolism; Animals; Clustered Regularly Interspaced Short Palindromic Repeats; Female; Glycolysis - genetics; Glycolysis - physiology; HeLa Cells; Humans; Kaplan-Meier Estimate; Methyltransferases - genetics; Methyltransferases - metabolism; Mice, Inbred BALB C; Promoter Regions, Genetic; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - genetics; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism; RNA Stability; RNA-Binding Proteins - metabolism; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - mortality; Xenograft Model Antitumor Assays
• ISSN: 2041-1723
• DOI: 10.1038/s41467-020-16306-5

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