O-GlcNAcylated FTO promotes m6A modification of SOX4 to enhance MDS/AML cell proliferation

Cell Commun Signal. 2025 Jan 23;23(1):43. doi: 10.1186/s12964-025-02058-6.

Abstract

Fat mass and obesity-associated protein (FTO) was the first m6A demethylase identified, which is responsible for eliminating m6A modifications in target RNAs. While it is well-established that numerous cytosolic and nuclear proteins undergo O-GlcNAcylation, the possibility of FTO being O-GlcNAcylated and its functional implications remain unclear. This study found that a negative correlation between FTO expression and O-GlcNAcylation in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The decreased O-GlcNAcylation on FTO can result in diminished m6A modification of SRY-related high mobility group box 4 (SOX4). This led to the promotion of cell apoptosis and inhibition of cell proliferation in MDS/AML. The O-GlcNAcylation of FTO stabilized SOX4 transcripts in an m6A-dependent manner, resulting in increased AKT and MAPK phosphorylation and decreased cell apoptosis. Inhibiting FTO O-GlcNAcylation significantly slowed AML progression in vitro, a finding supported by clinical data in MDS/AML patients. In conclusion, our study highlights the crucial role of FTO O-GlcNAcylation in RNA m6A methylation and the progression of MDS/AML, thereby providing a potential therapeutic avenue for these formidable diseases.

Keywords: Acute myeloid leukemia (AML); Fat mass and obesity-associated protein (FTO); Myelodysplastic syndromes (MDS); O-linked N-acetyglucosamine (O-GlcNAc); SRY related high mobility group box (SOX4).

MeSH terms

  • Adenosine* / analogs & derivatives
  • Adenosine* / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO* / metabolism
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Male
  • Myelodysplastic Syndromes* / genetics
  • Myelodysplastic Syndromes* / metabolism
  • Myelodysplastic Syndromes* / pathology
  • SOXC Transcription Factors* / genetics
  • SOXC Transcription Factors* / metabolism

Substances

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • SOXC Transcription Factors
  • FTO protein, human
  • SOX4 protein, human
  • N-methyladenosine
  • Adenosine