O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner

Cell Death Dis. 2025 Jul 12;16(1):518. doi: 10.1038/s41419-025-07844-1.

Abstract

The m6A methyltransferase METTL3 is a key regulator of RNA m6A modification, which plays a critical role in cancer development. Despite the significance of METTL3 in hepatocellular carcinoma (HCC), its post-translational modifications and their functional implications in HCC remain poorly understood. The present study reveals that METTL3 undergoes O-GlcNAcylation, which enhances its stability and promotes HCC progression. Specific O-GlcNAcylation sites (T186/S192/S193) in METTL3 are identified. O-GlcNAc modification reduces METTL3 ubiquitination, thereby increasing protein stability, and enhances its interaction with WTAP, thereby sustaining m6A levels in hepatoma cells. Notably, METTL3 O-GlcNAcylation upregulates the expression of minichromosome maintenance protein 10 (MCM10) by stabilizing its mRNA via an m6A-IGF2BP3-dependent manner. Targeting METTL3 O-GlcNAcylation with designed peptides effectively inhibits HCC growth both in vitro and in vivo. Collectively, our findings provide insights into the regulatory role of O-GlcNAcylation in modulating the m6A epitranscriptome and suggest the potential therapeutic relevance of targeting METTL3 O-GlcNAcylation in HCC.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Animals
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Methyltransferases* / genetics
  • Methyltransferases* / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Minichromosome Maintenance Proteins* / genetics
  • Minichromosome Maintenance Proteins* / metabolism
  • Protein Processing, Post-Translational
  • RNA Splicing Factors
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Ubiquitination
  • Up-Regulation

Substances

  • METTL3 protein, human
  • Methyltransferases
  • RNA-Binding Proteins
  • Minichromosome Maintenance Proteins
  • N-methyladenosine
  • IGF2BP3 protein, human
  • Adenosine
  • WTAP protein, human
  • RNA Splicing Factors
  • Cell Cycle Proteins