USP18 deubiquitinates and stabilizes SOX9 to promote the stemness and malignant progression of glioblastoma.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-05-15 DOI:10.1038/s41420-025-02522-9

Zhiyuan Liu, Kuo Yu, Kaile Chen, Yi Zhang, Kexiang Dai, Liang Zhao, Peng Zhao

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引用次数: 0

Abstract

Glioblastoma (GBM), the most common and aggressive primary brain tumour, is associated with poor prognosis, primarily due to its stem-like subpopulation, glioblastoma stem cells (GSCs). The deubiquitinase (DUB) family has attracted an increasing amount of attention due to its roles in GSC biology and tumour aggressiveness. In this study, we focused on ubiquitin-specific peptidase 18 (USP18), a member of the DUB family whose role in GBM is poorly understood. Through integrated bioinformatics analyses and experimental investigations using patient-derived samples, cell models, and animal models, we elucidated the role of USP18 in enhancing GSC stemness and promoting malignant behaviours. Our findings revealed that USP18 expression is significantly elevated in GBM and is correlated with a poor prognosis. Mechanistically, USP18 interacts with SRY-box transcription factor 9 (SOX9), stabilising its protein levels by cleaving K48-linked polyubiquitin chains. Additionally, we identified YY1 as a transcriptional regulator of USP18, increasing its expression in GBM cells. These findings reveal that USP18 is a potential therapeutic target and highlight the novel YY1/USP18/SOX9 signalling axis implicated in GBM progression.

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USP18去泛素化并稳定SOX9，促进胶质母细胞瘤的干性和恶性进展。

胶质母细胞瘤（GBM）是最常见和侵袭性最强的原发性脑肿瘤，其预后较差，主要是由于其干细胞样亚群胶质母细胞瘤干细胞（GSCs）。去泛素酶（deubiquitinase， DUB）家族因其在GSC生物学和肿瘤侵袭性中的作用而受到越来越多的关注。在这项研究中，我们关注的是泛素特异性肽酶18 (USP18)，它是DUB家族的一员，在GBM中的作用尚不清楚。通过综合生物信息学分析和实验研究，利用患者来源的样本、细胞模型和动物模型，我们阐明了USP18在增强GSC干性和促进恶性行为中的作用。我们的研究结果显示，USP18在GBM中的表达显著升高，并与预后不良相关。在机制上，USP18与SRY-box转录因子9 （SOX9）相互作用，通过切割k48连接的多泛素链来稳定其蛋白水平。此外，我们发现YY1是USP18的转录调节因子，增加其在GBM细胞中的表达。这些发现表明USP18是一个潜在的治疗靶点，并强调了新的YY1/USP18/SOX9信号轴与GBM进展有关。

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

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.