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

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

doi:10.1038/s41467-025-56633-z

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.

Authors

Na Zhang¹, Yang Meng^{2

3}, Song Mao¹, Huiling Ni^{1

2}, Canhua Huang¹, Licong Shen¹, Kun Fu¹, Lu Lv¹, Chunhong Yu¹, Piyanat Meekrathok¹, Chunmei Kuang¹, Fang Chen¹, Yu Zhang¹, 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. yuankai@csu.edu.cn.
⁵ Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, China. yuankai@csu.edu.cn.
⁶ Furong Laboratory, Changsha, 410008, China. yuankai@csu.edu.cn.
⁷ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, China. yuankai@csu.edu.cn.
⁸ The Biobank of Xiangya Hospital, Central South University, Changsha, 410000, China. yuankai@csu.edu.cn.

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.

MeSH terms

Acetylglucosamine / metabolism
Animals
Cell Line, Tumor
Cell Proliferation
Endometrial Neoplasms* / genetics
Endometrial Neoplasms* / metabolism
Endometrial Neoplasms* / pathology
Female
Gene Expression Regulation, Neoplastic
Glycosylation
Homeostasis
Humans
Mice
N-Acetylglucosaminyltransferases* / genetics
N-Acetylglucosaminyltransferases* / metabolism
Organoids / metabolism
Protein Processing, Post-Translational
Ubiquitination

Substances

N-Acetylglucosaminyltransferases
OGT protein, human
O-GlcNAc transferase
Acetylglucosamine

Abstract

MeSH terms

Substances

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