Center for Laboratory Medicine, Allergy Center, Department of Transfusion Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China; Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China; Hangzhou Chinese Academy of Sciences-Hangzhou Medical College Advanced Medical Technology Institute, Hangzhou, 310014, China.
Center for Laboratory Medicine, Allergy Center, Department of Transfusion Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China.
Redox Biol. 2022 Oct;56:102451. doi: 10.1016/j.redox.2022.102451. Epub 2022 Aug 28.
Glioblastoma is one of the most common intracranial malignant tumors with an unfavorable prognosis, and iron metabolism as well as ferroptosis are implicated in the pathogenesis of glioblastoma. The present study aims to decipher the role and mechanisms of tripartite motif-containing protein 7 (TRIM7) in ferroptosis and glioblastoma progression.
Stable TRIM7-deficient or overexpressing human glioblastoma cells were generated with lentiviral vectors, and cell survival, lipid peroxidation and iron metabolism were evaluated. Immunoprecipitation, protein degradation and ubiquitination assays were performed to demonstrate the regulation of TRIM7 on its candidate proteins.
TRIM7 expression was elevated in human glioblastoma cells and tissues. TRIM7 silence suppressed growth and induced death, while TRIM7 overexpression facilitated growth and inhibited death of human glioblastoma cells. Meanwhile, TRIM7-silenced cells exhibited increased iron accumulation, lipid peroxidation and ferroptosis, which were significantly reduced by TRIM7 overexpression. Mechanistically, TRIM7 directly bound to and ubiquitinated nuclear receptor coactivator 4 (NCOA4) using K48-linked chains, thereby reducing NCOA4-mediated ferritinophagy and ferroptosis of human glioblastoma cells. Moreover, we found that TRIM7 deletion sensitized human glioblastoma cells to temozolomide therapy.
We for the first time demonstrate that TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells, and our findings provide a novel insight into the progression and treatment for human glioblastoma.
胶质母细胞瘤是最常见的颅内恶性肿瘤之一，预后不良，铁代谢和铁死亡与胶质母细胞瘤的发病机制有关。本研究旨在阐明三结构域蛋白 7（TRIM7）在铁死亡和胶质母细胞瘤进展中的作用和机制。
利用慢病毒载体构建稳定的 TRIM7 缺陷或过表达的人胶质母细胞瘤细胞系，评估细胞存活、脂质过氧化和铁代谢。通过免疫沉淀、蛋白降解和泛素化实验来证明 TRIM7 对其候选蛋白的调控作用。
TRIM7 在人胶质母细胞瘤细胞和组织中表达上调。TRIM7 沉默抑制生长并诱导细胞死亡，而过表达 TRIM7 则促进生长并抑制细胞死亡。同时，沉默 TRIM7 的细胞表现出铁积累增加、脂质过氧化和铁死亡，而过表达 TRIM7 则显著降低了这些现象。机制上，TRIM7 直接结合并通过 K48 连接的链泛素化核受体共激活因子 4（NCOA4），从而减少 NCOA4 介导的铁蛋白自噬和铁死亡。此外，我们发现 TRIM7 缺失可使人类胶质母细胞瘤细胞对替莫唑胺治疗敏感。
我们首次证明 TRIM7 调节胶质母细胞瘤细胞中 NCOA4 介导的铁蛋白自噬和铁死亡，我们的研究结果为人类胶质母细胞瘤的进展和治疗提供了新的见解。
