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 and Kai Yuan ()
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Na Zhang: Central South University
Yang Meng: Central South University
Song Mao: Central South University
Huiling Ni: 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

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56633-z

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