Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Biol Ther. 2010 Oct 15;10(8):788-95. doi: 10.4161/cbt.10.8.12913.
Enhancer of Zeste Homologue 2 (EZH2), a specific histone 3 lysine 27 (H3K27) methyltransferase, plays a critical role in tumorigenesis and cancer progression through epigenetic gene silencing and chromatin remodeling. However, the role of EZH2 in chemotherapy resistance is unknown. In this study, we found that EZH2 was overexpressed in cisplatin-resistant ovarian cancer cells compared with cisplatin-sensitive cells. Knockdown of EZH2 by RNA interference (RNAi) resensitized drug-resistant ovarian cancer A2780/DDP cells to cisplatin and decreased the level of H3K27 trimethylation (H3K27me3). Moreover, EZH2 downregulation suppressed cell proliferation and caused G2/M cell cycle arrest in A2780/DDP cells. Loss of EZH2 also enhanced sensibility of tumor xenografts to cisplatin and inhibited tumor growth in vivo. Our results indicate that EZH2 is essential for chemotherapy resistance in cisplatin-resistant cancer cells in vitro and in vivo, which is probably through H3K27 methylation as well as regulation of cell proliferation. EZH2 could be a potential novel epigenetic target to overcome drug resistance.
增强子结合锌指蛋白 2（EZH2）是一种特异性的组蛋白 3 赖氨酸 27（H3K27）甲基转移酶，通过表观遗传学基因沉默和染色质重塑，在肿瘤发生和癌症进展中发挥关键作用。然而，EZH2 在化疗耐药中的作用尚不清楚。在本研究中，我们发现与顺铂敏感细胞相比，EZH2 在顺铂耐药卵巢癌细胞中过度表达。用 RNA 干扰（RNAi）敲低 EZH2 可使耐药性卵巢癌细胞 A2780/DDP 对顺铂重新敏感，并降低 H3K27 三甲基化（H3K27me3）水平。此外，EZH2 下调抑制 A2780/DDP 细胞的增殖并导致 G2/M 细胞周期停滞。EZH2 的缺失还增强了肿瘤异种移植物对顺铂的敏感性，并抑制了体内肿瘤的生长。我们的结果表明，EZH2 对于体外和体内顺铂耐药癌细胞的化疗耐药是必需的，这可能是通过 H3K27 甲基化以及对细胞增殖的调节。EZH2 可能是克服耐药性的潜在新型表观遗传靶点。
