Long Yu, Hu Zengchun, Yang Dian, Wang Fuqiang, Zhao Chen'ge, Zhang Yang, Zhang Yingqiu, Ma Hui, Lv Huiyi
Department of Pharmacy, The Second Affiliated Hospital, Dalian Medical University, No. 467 Zhongshan Road, Dalian 116000, China.
Department of Neurosurgery, The Second Affiliated Hospital, Dalian Medical University, Dalian 116000, China.
Open Life Sci. 2023 Feb 9;18(1):20220562. doi: 10.1515/biol-2022-0562. eCollection 2023.
Glioblastoma (GBM) is a malignant brain tumor. The purpose of this study is to estimate the potential effects and underlying mechanisms of a ubiquitin-specific protease 8 (USP8) small-molecule inhibitor on the phenotypic characteristics of GBM cells. The growth, migration, invasion, and stemness of GBM LN229 and T98G cells were evaluated by conducting cell proliferation, colony formation, wound healing, transwell, Ki-67 staining, spheroid formation, and ionizing radiation assays, and the results collectively showed the suppressive effects of USP8 inhibition on GBM cells. Furthermore, transcriptomic profiling of GBM cells treated with the USP8 inhibitor deubiquitinase (DUB)-IN-1 revealed significantly altered mRNA expression induced by pharmacological USP8 inhibition, from which we confirmed downregulated Aurora kinase A (AURKA) protein levels using immunoblotting assays. Our findings indicated that the proliferation, invasion, and stemness of LN229 and T98G cells were markedly suppressed by USP8 inhibition. Pharmacological USP8 suppression elicits multiple tumor-inhibitory effects, likely through dysregulating various mRNA expression events, including that of the key cell cycle regulator and oncogenic protein AURKA. Therefore, our observations corroborate the GBM-supportive roles of USP8 and suggest pharmacological USP8 inhibition is a viable therapeutic approach to target GBM. The purpose of this study was to investigate the effect and mechanism of action of the USP8 inhibitor DUB-IN-1 on GBM.
胶质母细胞瘤（GBM）是一种恶性脑肿瘤。本研究的目的是评估泛素特异性蛋白酶8（USP8）小分子抑制剂对GBM细胞表型特征的潜在影响及潜在机制。通过进行细胞增殖、集落形成、伤口愈合、Transwell、Ki-67染色、球体形成和电离辐射试验，评估了GBM LN229和T98G细胞的生长、迁移、侵袭和干性，结果共同显示了USP8抑制对GBM细胞的抑制作用。此外，用USP8抑制剂去泛素化酶（DUB）-IN-1处理的GBM细胞的转录组分析显示，药理学上抑制USP8可显著改变mRNA表达，我们通过免疫印迹试验证实了极光激酶A（AURKA）蛋白水平下调。我们的研究结果表明，USP8抑制可显著抑制LN229和T98G细胞的增殖、侵袭和干性。药理学上抑制USP8可引发多种肿瘤抑制作用，可能是通过调节各种mRNA表达事件失调，包括关键细胞周期调节因子和致癌蛋白AURKA的表达。因此，我们的观察结果证实了USP8对GBM的支持作用，并表明药理学上抑制USP8是一种可行的靶向GBM的治疗方法。本研究的目的是研究USP8抑制剂DUB-IN-1对GBM的作用效果及作用机制。
