Department of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning 110112, P.R. China.
Department of Breast Surgery and Surgical Oncology, Research Unit of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Mol Med Rep. 2018 Feb;17(2):2642-2650. doi: 10.3892/mmr.2017.8160. Epub 2017 Nov 27.
Enhancer of zeste homologue 2 (EZH2), a catalytic subunit of polycomb repressive complex 2, is overexpressed in a number of different tumors including breast cancer, and serves important roles in cell cycle regulation, proliferation, apoptosis, tumorigenesis and drug resistance. However, it remains unclear whether EZH2 contributes to tamoxifen resistance in breast cancer. In the present study, the role of EZH2 in tamoxifen resistance in MCF‑7 cells was investigated. EZH2 was overexpressed in MCF‑7 tamoxifen‑resistant (MCF‑7 TamR) cells. EZH2 overexpression decreased the sensitivity of MCF‑7 cells to tamoxifen, and EZH2 knockdown improved the sensitivity of MCF‑7 TamR cells to tamoxifen. Furthermore, EZH2 knockdown induced cell cycle arrest in MCF‑7 TamR cells, accompanied by a decrease in cyclin D1 expression and an increase in p16 expression. EZH2 knockdown reduced p16 gene methylation in MCF‑7 TamR cells. These findings suggested that EZH2 overexpression may contribute to tamoxifen resistance in breast cancer, and EZH2 inhibition may reverse tamoxifen resistance in breast cancer by regulating the cell cycle via the demethylation of the p16 gene. Thus, EZH2 inhibitors may be effective for treating tamoxifen resistance in breast cancer.
增强子结合锌指蛋白 2（EZH2）是多梳抑制复合物 2 的催化亚基，在包括乳腺癌在内的许多不同肿瘤中过表达，并在细胞周期调控、增殖、凋亡、肿瘤发生和耐药性中发挥重要作用。然而，EZH2 是否有助于乳腺癌对他莫昔芬的耐药性仍不清楚。在本研究中，研究了 EZH2 在 MCF-7 细胞对他莫昔芬耐药性中的作用。EZH2 在 MCF-7 他莫昔芬耐药（MCF-7 TamR）细胞中过表达。EZH2 的过表达降低了 MCF-7 细胞对他莫昔芬的敏感性，而 EZH2 的敲低则提高了 MCF-7 TamR 细胞对他莫昔芬的敏感性。此外，EZH2 的敲低诱导 MCF-7 TamR 细胞的细胞周期停滞，伴随 cyclin D1 表达降低和 p16 表达增加。EZH2 的敲低降低了 MCF-7 TamR 细胞中 p16 基因的甲基化。这些发现表明，EZH2 的过表达可能有助于乳腺癌对他莫昔芬的耐药性，EZH2 的抑制可能通过 p16 基因的去甲基化来调节细胞周期从而逆转乳腺癌对他莫昔芬的耐药性。因此，EZH2 抑制剂可能对治疗乳腺癌对他莫昔芬的耐药性有效。
