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RNA m1A methylation regulates glycolysis of cancer cells through modulating ATP5D

Yingmin Wu1,2, Zhuojia Chen3, Guoyou Xie1

  • 1Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Proceedings of the National Academy of Sciences of the United States of America
|July 22, 2022
PubMed

Insights

N1-methyladenosine (m1A) demethylase ALKBH3 regulates cancer cell glycolysis by targeting ATP5D. This RNA modification impacts tumor growth and cancer progression, revealing a link between mRNA metabolism and cancer therapeutics.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • While N6-methyladenosine (m6A) modifications in mRNA are well-studied, the role of N1-methyladenosine (m1A) in cancer progression is largely unknown.
  • Understanding RNA modifications' impact on cellular metabolism is crucial for developing novel cancer therapies.

Purpose of the Study:

  • To investigate the role of m1A demethylase ALKBH3 in cancer cell glycolysis.
  • To elucidate the mechanism by which ALKBH3 regulates cancer cell metabolism and tumor growth.

Main Methods:

  • Investigated ALKBH3's demethylase activity in cancer cell glycolysis.
  • Utilized sequencing and functional studies to identify ATP5D as a key regulator.
  • Employed the dm1ACRISPR system for targeted demethylation of ATP5D m1A.
  • Performed in vivo experiments to assess the role in tumor growth.

Main Results:

  • ALKBH3 regulates cancer cell glycolysis in a demethylation-dependent manner.
  • m1A modification at A71 of ATP5D negatively impacts its translation elongation via YTHDF1/eRF1 complex.
  • m1A also affects E2F1 mRNA stability, influencing ATP5D transcription.
  • Targeted demethylation of ATP5D m1A enhances ATP5D expression and glycolysis, promoting tumor growth.

Conclusions:

  • Reveals a novel mechanism linking mRNA m1A modification, specifically of ATP5D, to cancer cell glycolysis and progression.
  • Highlights the interplay between RNA modification and cell metabolism as a potential therapeutic target in cancer.
Keywords:
ATP5Dcancer cellm1Ametabolism

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