Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Oncogene. 2023 Jun;42(26):2103-2112. doi: 10.1038/s41388-023-02717-3. Epub 2023 May 15.
Resistance to temozolomide (TMZ) remains an important cause of treatment failure in patients with glioblastoma multiforme (GBM). TRIM25, as a tripartite motif-containing (TRIM) family member, plays a significant role in cancer progression and chemoresistance. However, the function of TRIM25 and its precise mechanism in regulating GBM progression and TMZ resistance remain poorly understood. We found that the expression of TRIM25 was upregulated in GBM, and it was associated with tumor grade and TMZ resistance. Elevated TRIM25 expression predicted a poor prognosis in GBM patients and enhanced tumor growth in vitro and in vivo. Further analysis revealed that elevated TRIM25 expression inhibited oxidative stress and ferroptotic cell death in glioma cells under TMZ treatment. Mechanistically, TRIM25 regulates TMZ resistance by promoting the nuclear import of nuclear factor erythroid 2-related factor 2(Nrf2) via keap1 ubiquitination. Knockdown of Nrf2 abolished the ability of TRIM25 to promote glioma cell survival and TMZ resistance. Our results support the targeting of TRIM25 as a new therapeutic strategy for glioma.
替莫唑胺（TMZ）耐药仍然是多形性胶质母细胞瘤（GBM）患者治疗失败的重要原因。TRIM25 作为三结构域蛋白（TRIM）家族的一员，在癌症进展和化疗耐药中发挥重要作用。然而，TRIM25 的功能及其在调节 GBM 进展和 TMZ 耐药中的精确机制仍知之甚少。我们发现 TRIM25 在 GBM 中表达上调，与肿瘤分级和 TMZ 耐药相关。TRIM25 表达升高预示着 GBM 患者预后不良，并增强了体外和体内的肿瘤生长。进一步分析表明，TRIM25 通过 KEAP1 泛素化促进核因子红细胞 2 相关因子 2（Nrf2）的核输入，从而抑制 TMZ 处理下的胶质瘤细胞氧化应激和铁死亡。机制上，TRIM25 通过 KEAP1 泛素化促进核因子红细胞 2 相关因子 2（Nrf2）的核输入来调节 TMZ 耐药。Nrf2 的敲低消除了 TRIM25 促进神经胶质瘤细胞存活和 TMZ 耐药的能力。我们的研究结果支持将 TRIM25 作为一种新的治疗胶质母细胞瘤的策略。
