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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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    1. Chunhong Yu & Xiaoyun Lei & Fang Chen & Song Mao & Lu Lv & Honglu Liu & Xueying Hu & Runhan Wang & Licong Shen & Na Zhang & Yang Meng & Yunfan Shen & Jiale Chen & Pishun Li & Shi Huang & Changwei Lin , 2022. "ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Xiao Zhang & Yongxia Qiao & Qi Wu & Yan Chen & Shaowu Zou & Xiangfan Liu & Guoqing Zhu & Yinghui Zhao & Yuxin Chen & Yongchun Yu & Qiuhui Pan & Jiayi Wang & Fenyong Sun, 2017. "The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    3. Takaaki Oba & Mark D. Long & Tibor Keler & Henry C. Marsh & Hans Minderman & Scott I. Abrams & Song Liu & Fumito Ito, 2020. "Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    4. Manas K. Santra & Narendra Wajapeyee & Michael R. Green, 2009. "F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage," Nature, Nature, vol. 459(7247), pages 722-725, June.
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