Liu Jiaqi, Wang Kaikai, Zhu Qian, Zhang Yixin, Chen Yuping, Lou Zhenkun, Yuan Jian
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
CNS Neurosci Ther. 2024 Apr;30(4):e14711. doi: 10.1111/cns.14711.
To elucidate the relationship between USP19 and O(6)-methylguanine-DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with chemotherapy resistance.
Screening the deubiquitinase pannel and identifying the deubiquitinase directly interacts with and deubiquitination MGMT. Deubiquitination assay to confirm USP19 deubiquitinates MGMT. The colony formation and tumor growth study in xenograft assess USP19 affects the GBM sensitive to TMZ was performed by T98G, LN18, U251, and U87 cell lines. Immunohistochemistry staining and survival analysis were performed to explore how USP19 is correlated to MGMT in GBM clinical management.
USP19 removes the ubiquitination of MGMT to facilitate the DNA methylation damage repair. Depletion of USP19 results in the glioblastoma cell sensitivity to temozolomide, which can be rescued by overexpressing MGMT. USP19 is overexpressed in glioblastoma patient samples, which positively correlates with the level of MGMT protein and poor prognosis in these patients.
The regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients' temozolomide chemotherapy response.
阐明在对化疗耐药的胶质母细胞瘤（GBM）患者中，替莫唑胺治疗后泛素特异性蛋白酶19（USP19）与O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）之间的关系。
筛选去泛素酶面板并鉴定与MGMT直接相互作用并使其去泛素化的去泛素酶。进行去泛素化试验以确认USP19使MGMT去泛素化。通过T98G、LN18、U251和U87细胞系在异种移植中进行集落形成和肿瘤生长研究，以评估USP19对替莫唑胺敏感的GBM的影响。进行免疫组织化学染色和生存分析，以探讨在GBM临床管理中USP19与MGMT的相关性。
USP19去除MGMT的泛素化以促进DNA甲基化损伤修复。USP19的缺失导致胶质母细胞瘤细胞对替莫唑胺敏感，而过表达MGMT可挽救这种敏感性。USP19在胶质母细胞瘤患者样本中过表达，这与这些患者中MGMT蛋白水平和不良预后呈正相关。
USP19对MGMT泛素化的调节在DNA甲基化损伤修复和GBM患者的替莫唑胺化疗反应中起关键作用。
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