Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, No. 55, Section 4, South Renmin Road, Chengdu, 610041, China.
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Mol Cell Biochem. 2024 Apr;479(4):831-841. doi: 10.1007/s11010-023-04767-3. Epub 2023 May 18.
Metastasis is the cause of poor prognosis in ovarian cancer (OC). Enhancer of Zeste homolog 2 (EZH2), a histone-lysine N-methyltransferase enzyme, promotes OC cell migration and invasion by regulating the expression of tissue inhibitor of metalloproteinase-2 (TIMP2) and matrix metalloproteinases-9 (MMP9). Hence, we speculated that EZH2-targeting therapy might suppress OC migration and invasion. In this study, the expression of EZH2, TIMP2, and MMP9 in OC tissues and cell lines was analyzed using The Cancer Genome Atlas (TCGA) database and western blotting, respectively. The effects of SKLB-03220, an EZH2 covalent inhibitor, on OC cell migration and invasion were investigated using wound-healing assays, Transwell assays, and immunohistochemistry. TCGA database analysis confirmed that the EZH2 and MMP9 mRNA expression was significantly higher in OC tissues, whereas TIMP2 expression was significantly lower than that in normal ovarian tissues. Moreover, EZH2 negatively correlated with TIMP2 and positively correlated with MMP9 expression. In addition to the anti-tumor activity of SKLB-03220 in a PA-1 xenograft model, immunohistochemistry results showed that SKLB-03220 markedly increased the expression of TIMP2 and decreased the expression of MMP9. Additionally, wound-healing and Transwell assays showed that SKLB-03220 significantly inhibited the migration and invasion of both A2780 and PA-1 cells in a concentration-dependent manner. SKLB-03220 inhibited H3K27me3 and MMP9 expression and increased TIMP2 expression in PA-1 cells. Taken together, these results indicate that the EZH2 covalent inhibitor SKLB-03220 inhibits metastasis of OC cells by upregulating TIMP2 and downregulating MMP9, and could thus serve as a therapeutic agent for OC.
转移是卵巢癌 (OC) 预后不良的原因。EZH2（一种组蛋白赖氨酸 N-甲基转移酶酶）通过调节组织抑制剂金属蛋白酶-2 (TIMP2) 和基质金属蛋白酶-9 (MMP9) 的表达，促进 OC 细胞迁移和侵袭。因此，我们推测 EZH2 靶向治疗可能会抑制 OC 的迁移和侵袭。在这项研究中，使用癌症基因组图谱 (TCGA) 数据库和 Western blot 分别分析了 OC 组织和细胞系中 EZH2、TIMP2 和 MMP9 的表达。使用划痕愈合试验、Transwell 试验和免疫组织化学法研究了 EZH2 共价抑制剂 SKLB-03220 对 OC 细胞迁移和侵袭的影响。TCGA 数据库分析证实，EZH2 和 MMP9 mRNA 的表达在 OC 组织中明显升高，而 TIMP2 的表达明显低于正常卵巢组织。此外，EZH2 与 TIMP2 呈负相关，与 MMP9 呈正相关。除了 SKLB-03220 在 PA-1 异种移植模型中的抗肿瘤活性外，免疫组织化学结果表明，SKLB-03220 显著增加了 TIMP2 的表达并降低了 MMP9 的表达。此外，划痕愈合和 Transwell 试验表明，SKLB-03220 以浓度依赖性方式显著抑制 A2780 和 PA-1 细胞的迁移和侵袭。SKLB-03220 抑制 H3K27me3 和 MMP9 表达，上调 PA-1 细胞中的 TIMP2 表达。综上所述，这些结果表明，EZH2 共价抑制剂 SKLB-03220 通过上调 TIMP2 和下调 MMP9 抑制 OC 细胞的转移，可作为 OC 的治疗药物。
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