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FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy

Author

Listed:
  • Na Zhang

    (Central South University)

  • Yang Meng

    (Central South University
    Tsinghua University)

  • Song Mao

    (Central South University)

  • Huiling Ni

    (Central South University
    Central South University)

  • Canhua Huang

    (Central South University)

  • Licong Shen

    (Central South University)

  • Kun Fu

    (Central South University)

  • Lu Lv

    (Central South University)

  • Chunhong Yu

    (Central South University)

  • Piyanat Meekrathok

    (Central South University)

  • Chunmei Kuang

    (Central South University)

  • Fang Chen

    (Central South University)

  • Yu Zhang

    (Central South University)

  • Kai Yuan

    (Central South University
    Central South University
    Furong Laboratory
    Central South University)

Abstract

Protein O-GlcNAcylation is a post-translational modification coupled to cellular metabolic plasticity. Aberrant O-GlcNAcylation has been observed in many cancers including endometrial cancer (EC), a common malignancy in women. However, clinical characterization of dysregulated O-GlcNAcylation homeostasis in EC and interrogating its molecular mechanism remain incomplete. Here we report that O-GlcNAcylation level is positively correlated with EC histologic grade in a Chinese cohort containing 219 tumors, validated in The Cancer Genome Atlas dataset. Increasing O-GlcNAcylation in patient-derived endometrial epithelial organoids promotes proliferation and stem-like cell properties, whereas decreasing O-GlcNAcylation limits the growth of endometrial cancer organoids. CRISPR screen and biochemical characterization reveal that tumor suppressor F-box only protein 31 (FBXO31) regulates O-GlcNAcylation homeostasis in EC by ubiquitinating the O-GlcNAc transferase OGT. Downregulation of O-GlcNAcylation impedes EC tumor formation in mouse models. Collectively, our study highlights O-GlcNAcylation as a useful stratification marker and a therapeutic vulnerability for the advanced, poorly differentiated EC cases.

Suggested Citation

  • Na Zhang & Yang Meng & Song Mao & Huiling Ni & Canhua Huang & Licong Shen & Kun Fu & Lu Lv & Chunhong Yu & Piyanat Meekrathok & Chunmei Kuang & Fang Chen & Yu Zhang & Kai Yuan, 2025. "FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56633-z
    DOI: 10.1038/s41467-025-56633-z
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    References listed on IDEAS

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