Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Zhejiang Province, Jinhua, 321000, China.
Department of Pathology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Zhejiang Province, Jinhua, 321000, China.
J Mol Neurosci. 2022 Sep;72(9):2030-2044. doi: 10.1007/s12031-022-02051-5. Epub 2022 Aug 8.
SET and MYND domain-containing protein 2 (SMYD2) is an important epigenetic regulator that methylates histone and non-histone proteins. The study aimed to investigate the oncogenic role of SMYD2 in gliomas and explore its degradation mechanism induced by cisplatin. Tumor tissue microarray of 441 patients with glioma was collected for SMYD2 immunohistochemical staining. Kaplan-Meier survival curves were constructed using the overall survival values. mRNA-sequencing analysis was performed for understanding the downstream mechanisms mediated by SMYD2. The half-inhibitory concentrations (IC50) of temozolomide and cisplatin in AZ505-treated and control cells were calculated. The potential E3 ubiquitin ligase of SMYD2 was predicted in UbiBrowser and confirmed by a knockdown test. The effect of SMYD2 and its E3 ligase on apoptosis and migration of glioma cells was determined via cell-function assays. High SMYD2 expression correlated with a high WHO stage (P = 0.004) and a low survival probability (P = 0.012). The inhibition of SMYD2 suppressed the process of epithelial to mesenchymal transition (EMT) by downregulating the expression of Collagen 1A1 (COL1A1). AZ505 treatment significantly increased the drug sensitivity of glioma cells. SMYD2 expression was markedly reduced by cisplatin treatment via STIP1 Homology And U-Box Containing Protein 1 (STUB1)-mediated degradation. The knockdown of STUB1 could partly reverse the cell function impairment induced by cisplatin. Our findings suggested that SMYD2 could be a potential drug target for the treatment of gliomas, and STUB1-mediated degradation of SMYD2 plays an important role in reversing chemotherapy resistance in patients with gliomas.
SET 结构域和 MYND 结构域蛋白 2（SMYD2）是一种重要的表观遗传调节因子，可甲基化组蛋白和非组蛋白。本研究旨在探讨 SMYD2 在神经胶质瘤中的致癌作用及其对顺铂诱导的降解机制。收集了 441 例神经胶质瘤患者的肿瘤组织微阵列，进行 SMYD2 免疫组织化学染色。根据总生存值绘制 Kaplan-Meier 生存曲线。进行 mRNA 测序分析以了解 SMYD2 介导的下游机制。计算 AZ505 处理和对照细胞中替莫唑胺和顺铂的半抑制浓度（IC50）。在 UbiBrowser 中预测 SMYD2 的潜在 E3 泛素连接酶，并通过敲低试验进行验证。通过细胞功能测定确定 SMYD2 及其 E3 连接酶对神经胶质瘤细胞凋亡和迁移的影响。SMYD2 高表达与较高的 WHO 分期（P = 0.004）和较低的生存概率（P = 0.012）相关。SMYD2 的抑制通过下调 Collagen 1A1（COL1A1）的表达抑制上皮间质转化（EMT）过程。AZ505 处理显著增加了神经胶质瘤细胞的药物敏感性。顺铂通过 STIP1 同源和 U -box 包含蛋白 1（STUB1）介导的降解显著降低 SMYD2 表达。STUB1 的敲低可以部分逆转顺铂引起的细胞功能障碍。我们的研究结果表明，SMYD2 可能是治疗神经胶质瘤的潜在药物靶点，STUB1 介导的 SMYD2 降解在逆转神经胶质瘤患者化疗耐药中起重要作用。
