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

  • Nat Commun. 2025 Feb 2;16(1):1274. doi: 10.1038/s41467-025-56633-z.
Na Zhang  1 ,  Yang Meng  2  3 ,  Song Mao  1 ,  Huiling Ni  1  2 ,  Canhua Huang  1 ,  Licong Shen  1 ,  Kun Fu  1 ,  Lu Lv  1 ,  Chunhong Yu  1 ,  Piyanat Meekrathok  1 ,  Chunmei Kuang  1 ,  Fang Chen  1 ,  Yu Zhang  1 ,  Kai Yuan  4  5  6  7  8
Affiliations
  • 1. Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South University, Changsha, 410000, China.
  • 2. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, China.
  • 3. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
  • 4. Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South University, Changsha, 410000, China. [email protected].
  • 5. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, China. [email protected].
  • 6. Furong Laboratory, Changsha, 410008, China. [email protected].
  • 7. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, China. [email protected].
  • 8. The Biobank of Xiangya Hospital, Central South University, Changsha, 410000, China. [email protected].
PMID: 39894887 DOI: 10.1038/s41467-025-56633-z
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.

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