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

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2025-02-02 DOI:10.1038/s41467-025-56633-z

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

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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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fbxo31介导的OGT泛素化维持o - glcn酰化稳态以抑制子宫内膜恶性肿瘤

蛋白o - glcn酰化是一种与细胞代谢可塑性相关的翻译后修饰。异常的o - glcn酰化已经在许多癌症中被观察到，包括子宫内膜癌（EC），一种常见的女性恶性肿瘤。然而，EC中o - glcn酰化稳态失调的临床特征及其分子机制尚不完整。在此，我们报告了在包含219个肿瘤的中国队列中，o - glcnac酰化水平与EC组织学分级呈正相关，并在癌症基因组图谱数据集中得到验证。在患者来源的子宫内膜上皮类器官中，增加o - glcn酰化可促进增殖和干细胞样细胞特性，而减少o - glcn酰化则限制子宫内膜癌类器官的生长。CRISPR筛选和生化鉴定显示，肿瘤抑制因子F-box only蛋白31 （FBXO31）通过泛素化O-GlcNAc转移酶OGT来调节EC中O-GlcNAc酰化的稳态。在小鼠模型中，下调o - glcn酰化抑制EC肿瘤的形成。总的来说，我们的研究强调了o - glcn酰化是一种有用的分层标志物，也是晚期、低分化EC病例的治疗脆弱性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.