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N6-methyladenosine regulates glycolysis of cancer cells through PDK4

Zihan Li1,2, Yanxi Peng1,3, Jiexin Li1

  • 1Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.

Nature Communications
|May 24, 2020
PubMed

Insights

N6-methyladenosine (m6A) RNA modification promotes cancer cell glycolysis by upregulating pyruvate dehydrogenase kinase 4 (PDK4). Inhibiting m6A modification of PDK4 reduces cancer cell glycolysis and tumor progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) is a prevalent mRNA modification influencing gene expression.
  • Dysregulation of cellular metabolism, particularly glycolysis, is a hallmark of cancer.

Purpose of the Study:

  • To investigate the role of m6A modification in regulating cancer cell glycolysis.
  • To identify key molecules involved in m6A-mediated glycolysis regulation.

Main Methods:

  • m6A-sequencing
  • Functional assays
  • CRISPR-based demethylation system (dm6ACRISPR)
  • In vivo and clinical data analysis

Main Results:

  • m6A modification positively regulates cancer cell glycolysis and ATP generation.
  • Pyruvate dehydrogenase kinase 4 (PDK4) is identified as a key mediator of m6A-regulated glycolysis.
  • m6A modification of PDK4 enhances its translation elongation and mRNA stability.
  • Targeted demethylation of PDK4 m6A significantly reduces cancer cell glycolysis.
  • TATA-binding protein (TBP) upregulates Mettl3 expression in cervical cancer cells.
  • m6A/PDK4 signaling promotes tumor growth in cervical and liver cancer models.

Conclusions:

  • m6A modification plays a crucial role in promoting cancer cell glycolysis through the regulation of PDK4.
  • Targeting the m6A-PDK4 axis represents a potential therapeutic strategy for cancer treatment.

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