SAE1 通过激活 AKT SUMOylation 介导的信号通路促进人胶质瘤的进展。
SAE1 promotes human glioma progression through activating AKT SUMOylation-mediated signaling pathways.
机构信息
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, No.17, 3rd Section of People's South Road, Chengdu, 610041, People's Republic of China.
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
出版信息
Cell Commun Signal. 2019 Jul 25;17(1):82. doi: 10.1186/s12964-019-0392-9.
BACKGROUND
The SUMO-activating enzyme SAE1 is indispensable for protein SUMOylation. A dysregulation of SAE1 expression involves in progression of several human cancers. However, its biological roles of SAE1 in glioma are unclear by now.
METHODS
The differential proteome between human glioma tissues and para-cancerous brain tissues were identified by LC-MS/MS. SAE1 expression was further assessed by immunohistochemistry. The patient overall survival versus SAE1 expression level was evaluated by Kaplan-Meier method. The glioma cell growth and migration were evaluated under SAE1 overexpression or inhibition by the CCK8, transwell assay and wound healing analysis. The SUMO1 modified target proteins were enriched from total cellular or tissue proteins by incubation with the anti-SUMO1 antibody on protein-A beads overnight, then the SUMOylated proteins were detected by Western blot. Cell apoptosis and cell cycle were analyzed by flow cytometry. The nude mouse xenograft was determined glioma growth and tumorigenicity in vivo.
RESULTS
SAE1 is identified to increase in glioma tissues by a quantitative proteomic dissection, and SAE1 upregulation indicates a high level of tumor malignancy grade and a poor overall survival for glioma patients. SAE1 overexpression induces an increase of the SUMOylation and Ser473 phosphorylation of AKT, which promotes glioma cell growth in vitro and in nude mouse tumor model. On the contrary, SAE1 silence induces an obvious suppression of the SUMOylation and Ser473 phosphorylation of Akt, which inhibits glioma cell proliferation and the tumor xenograft growth through inducing cell cycle arrest at G2 phase and cell apoptosis driven by serial biochemical molecular events.
CONCLUSION
SAE1 promotes glioma cancer progression via enhancing Akt SUMOylation-mediated signaling pathway, which indicates targeting SUMOylation is a promising therapeutic strategy for human glioma.
背景
SUMO 激活酶 SAE1 对于蛋白质 SUMO 化是不可或缺的。SAE1 表达的失调涉及到几种人类癌症的进展。然而，SAE1 在神经胶质瘤中的生物学作用目前尚不清楚。
方法
通过 LC-MS/MS 鉴定人神经胶质瘤组织与癌旁脑组织之间的差异蛋白质组。通过免疫组织化学进一步评估 SAE1 的表达。通过 Kaplan-Meier 方法评估患者总生存期与 SAE1 表达水平的关系。通过 CCK8、Transwell 测定和划痕愈合分析评估 SAE1 过表达或抑制时神经胶质瘤细胞的生长和迁移。通过将抗 SUMO1 抗体孵育过夜在蛋白 A 珠上，从总细胞或组织蛋白中富集 SUMO1 修饰的靶蛋白，然后通过 Western blot 检测 SUMOylated 蛋白。通过流式细胞术分析细胞凋亡和细胞周期。裸鼠异种移植确定体内神经胶质瘤的生长和致瘤性。
结果
通过定量蛋白质组学分析发现 SAE1 在神经胶质瘤组织中增加，SAE1 的上调表明肿瘤恶性程度高，神经胶质瘤患者的总体生存率低。SAE1 过表达诱导 AKT 的 SUMOylation 和 Ser473 磷酸化增加，促进体外和裸鼠肿瘤模型中的神经胶质瘤细胞生长。相反，SAE1 沉默诱导 Akt 的 SUMOylation 和 Ser473 磷酸化明显抑制，通过一系列生化分子事件诱导细胞周期停滞在 G2 期和细胞凋亡，从而抑制神经胶质瘤细胞增殖和肿瘤异种移植生长。
结论
SAE1 通过增强 Akt SUMOylation 介导的信号通路促进神经胶质瘤的进展，这表明靶向 SUMOylation 是治疗人类神经胶质瘤的一种有前途的治疗策略。
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