Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde, 067000, Hebei, PR China.
Department of Neurosurgery, Affiliated Hospital of Chengde Medical University, Chengde, 067000, Hebei, PR China.
Exp Cell Res. 2023 Dec 15;433(2):113822. doi: 10.1016/j.yexcr.2023.113822. Epub 2023 Oct 21.
Gliomas are the most common primary brain tumors in adults. Although they exist in different malignant stages, most gliomas are clinically challenging because of their infiltrative growth patterns and inherent relapse tendency with increased malignancy. Epigenetic alterations have been suggested to be an important factor for glioma genesis. Using mRNA probe hybridization, we identified SUMO-specific protease 1 (SENP1) as the most significantly upregulated SUMOylation regulator in glioma. Moreover, SENP1 was overexpressed in gliomas and predicted poor prognoses. Depletion of SENP1 reduced glioma cell activity, cycle arrest, and increased apoptotic activity. Mechanistically, SENP1 inhibited the protein expression of sirtuin 1 (SIRT1) through de-SUMOylation, and SIRT1 inhibited the activity of nuclear factor kappaB (NF-κB) by deacetylation. Rescue experiments revealed that downregulation of SIRT1 reversed the inhibitory effect of sh-SENP1 on glioma cell malignant phenotype, while downregulation of NF-κB reversed the activating effect of sh-SIRT1 on glioma cell malignant phenotype. Thus, SENP1-mediated de-SUMOylation of SIRT1 might be therapeutically important in gliomas.
神经胶质瘤是成人中最常见的原发性脑肿瘤。尽管它们存在不同的恶性阶段，但由于其浸润性生长模式和固有复发倾向以及恶性程度增加，大多数神经胶质瘤在临床上都具有挑战性。表观遗传改变被认为是神经胶质瘤发生的一个重要因素。通过 mRNA 探针杂交，我们确定 SUMO 特异性蛋白酶 1（SENP1）是神经胶质瘤中最显著上调的 SUMOylation 调节剂。此外，SENP1 在神经胶质瘤中过表达，并预测预后不良。SENP1 的耗竭降低了神经胶质瘤细胞的活性、细胞周期停滞，并增加了细胞凋亡活性。在机制上，SENP1 通过去 SUMOylation 抑制了 SIRT1 蛋白的表达，而 SIRT1 通过去乙酰化抑制了核因子 kappaB（NF-κB）的活性。挽救实验表明，下调 SIRT1 逆转了 sh-SENP1 对神经胶质瘤细胞恶性表型的抑制作用，而下调 NF-κB 逆转了 sh-SIRT1 对神经胶质瘤细胞恶性表型的激活作用。因此，SENP1 介导的 SIRT1 的去 SUMOylation 在神经胶质瘤中可能具有重要的治疗意义。
