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

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月2日

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  • 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

摘要

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.