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Updated: Jun 8, 2025

A Method for Measuring RNA N6-methyladenosine Modifications in Cells and Tissues
08:56

A Method for Measuring RNA N6-methyladenosine Modifications in Cells and Tissues

Published on: December 5, 2016

10.9K

N6-Methyladenosine modification activates the serine synthesis pathway to mediate therapeutic resistance in liver

For-Fan Chan1, Kenneth Kin-Leung Kwan2, Do-Hyun Seoung2

  • 1State Key Laboratory of Liver Research and Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|November 3, 2024
PubMed

Insights

Targeting m6A modification of the serine synthesis pathway (SSP) inhibits hepatocellular carcinoma (HCC) growth and overcomes drug resistance. This study reveals m6A regulation of SSP enzymes, offering a potential therapeutic strategy for HCC.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Metabolic Pathways

Background:

  • Metabolic adaptation is crucial for cancer progression and treatment resistance.
  • The role of N6-methyladenosine (m6A) modification in hepatocellular carcinoma (HCC) remains incompletely understood.
  • Serine synthesis pathway (SSP) dysregulation contributes to cancer development.

Purpose of the Study:

  • To investigate the role of m6A-mediated regulation of the SSP in HCC.
  • To explore the potential of targeting m6A modification for HCC therapy and overcoming resistance.

Main Methods:

  • Treatment of HCC cell lines and mice with the m6A inhibitor STM2457.
  • GLORI-seq to map the m6A landscape in HCC.
  • Analysis of m6A modification, mRNA/protein expression of SSP enzymes (PHGDH, PSAT1, PSPH), and oxidative stress markers.

Main Results:

  • STM2457 inhibited HCC cell growth and spontaneous tumor formation in mice.
  • METTL3-mediated m6A modification of SSP enzymes (PHGDH, PSAT1, PSPH) was identified, stabilized by IGF2BP3.
  • Sorafenib-resistant HCC cells showed increased m6A modification in SSP genes, enhancing protein and antioxidant production; STM2457 reversed this, sensitizing cells to therapy.

Conclusions:

  • m6A modification of the serine synthesis pathway is a key driver of HCC development and therapeutic resistance.
  • Targeting m6A modification, particularly with inhibitors like STM2457, represents a promising therapeutic strategy for HCC.
  • This approach can overcome resistance to existing therapies by attenuating the SSP and inducing oxidative stress.
Keywords:
IGF2BP3METTL3SSP pathwaySTM2457TKI treatmentliver cancerm6Am6A modification

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