USP5 Stabilizes IKBKG Through Deubiquitination to Suppress Ferroptosis and Promote Growth in Non-small Cell Lung Cancer.

IF 1.8 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Biochemistry and Biophysics Pub Date : 2024-10-13 DOI:10.1007/s12013-024-01574-5
Yufu Li, Gan Qiu, Min Zhou, Qianzhi Chen, Xiaoyong Liao
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Abstract

Ferroptosis, a distinctive modality of cell mortality, has emerged as a critical regulator in non-small cell lung cancer (NSCLC). The deubiquitinating enzyme USP5 has established an oncogenic role in NSCLC. However, its biological relevance in NSCLC cell ferroptosis is currently unexplored. Expression analysis was performed by quantitative PCR (qPCR), immunohistochemistry (IHC) and immunoblotting. Animal xenograft studies were used to detect USP5's role in tumor growth. Cell proliferation, colony formation and apoptotic ratio were assessed by CCK-8, colony formation and flow cytometry assays, respectively. Cell ferroptosis was evaluated by gauging ROS, MDA, GSH, SOD, and Fe2+ contents. The USP5/IKBKG relationship and the ubiquitinated IKBKG were evaluated by Co-IP experiments. USP5 expression was elevated in human NSCLC. USP5 depletion suppressed NSCLC cell in vitro and in vivo growth and enhanced cell apoptosis. Moreover, USP5 depletion induced ferroptosis in NSCLC cell lines. Mechanistically, USP5 could enhance the stability of IKBKG protein through deubiquitination. Re-expression of IKBKG partially but significantly abolished USP5 depletion-mediated anti-growth and pro-ferroptosis effects in NSCLC cells. Our study demonstrates that USP5 suppresses ferroptosis and enhances growth in NSCLC cells by stabilizing IKBKG protein through deubiquitination. Targeting USP5 expression is an encouraging strategy to block NSCLC progression.

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USP5 通过去泛素化稳定 IKBKG,从而抑制非小细胞肺癌的铁变态反应并促进其生长。
非小细胞肺癌(NSCLC)的一个重要调节因素是铁蛋白沉积,这是一种独特的细胞死亡方式。去泛素化酶 USP5 在 NSCLC 中具有致癌作用。然而,它在 NSCLC 细胞铁蛋白沉积过程中的生物学相关性目前还未得到研究。表达分析是通过定量 PCR(qPCR)、免疫组织化学(IHC)和免疫印迹法进行的。动物异种移植研究用于检测 USP5 在肿瘤生长中的作用。细胞增殖、集落形成和凋亡比率分别通过 CCK-8、集落形成和流式细胞术测定法进行评估。通过检测 ROS、MDA、GSH、SOD 和 Fe2+ 的含量来评估细胞铁变态反应。通过 Co-IP 实验评估了 USP5/IKBKG 关系和泛素化的 IKBKG。USP5 在人类 NSCLC 中表达升高。消耗 USP5 可抑制 NSCLC 细胞的体外和体内生长,并增强细胞凋亡。此外,USP5 的缺失还诱导了 NSCLC 细胞系的铁凋亡。从机制上讲,USP5可通过去泛素化增强IKBKG蛋白的稳定性。IKBKG的再表达部分但显著地消除了USP5耗竭介导的NSCLC细胞抗生长和促铁细胞减少效应。我们的研究表明,USP5 通过去泛素化稳定 IKBKG 蛋白,从而抑制 NSCLC 细胞的铁变态反应并促进其生长。靶向 USP5 表达是阻止 NSCLC 进展的一种令人鼓舞的策略。
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来源期刊
Cell Biochemistry and Biophysics
Cell Biochemistry and Biophysics 生物-生化与分子生物学
CiteScore
4.40
自引率
0.00%
发文量
72
审稿时长
7.5 months
期刊介绍: Cell Biochemistry and Biophysics (CBB) aims to publish papers on the nature of the biochemical and biophysical mechanisms underlying the structure, control and function of cellular systems The reports should be within the framework of modern biochemistry and chemistry, biophysics and cell physiology, physics and engineering, molecular and structural biology. The relationship between molecular structure and function under investigation is emphasized. Examples of subject areas that CBB publishes are: · biochemical and biophysical aspects of cell structure and function; · interactions of cells and their molecular/macromolecular constituents; · innovative developments in genetic and biomolecular engineering; · computer-based analysis of tissues, cells, cell networks, organelles, and molecular/macromolecular assemblies; · photometric, spectroscopic, microscopic, mechanical, and electrical methodologies/techniques in analytical cytology, cytometry and innovative instrument design For articles that focus on computational aspects, authors should be clear about which docking and molecular dynamics algorithms or software packages are being used as well as details on the system parameterization, simulations conditions etc. In addition, docking calculations (virtual screening, QSAR, etc.) should be validated either by experimental studies or one or more reliable theoretical cross-validation methods.
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