Kim Min Young, Park Shin-Ji, Shim Jae Woong, Song Yu Jin, Yang Kwangmo, Park Seong-Joon, Heo Kyu
Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan 619-953, Republic of Korea.
Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Oncol Lett. 2017 Mar;13(3):1767-1774. doi: 10.3892/ol.2017.5626. Epub 2017 Jan 19.
BIX01294 (Bix) is known to be a euchromatic histone-lysine N-methyltransferase 2 inhibitor and treatment with Bix suppresses cancer cell survival and proliferation. In the present study, it was observed that sequential treatment with low-dose Bix notably increases glioblastoma cell migration and metastasis. It was demonstrated that U251 cells sequentially treated with low-dose Bix exhibited induced characteristic changes in critical epithelial-mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, β-catenin and zinc finger protein SNAI2. Notably, sequential treatment with Bix also increased the expression of cancer stem cell-associated markers, including sex determining region Y-box 2, octamer-binding transcription factor 4 and cluster of differentiation 133. Neurosphere formation was significantly enhanced in cells sequentially treated with Bix, compared with control cells (control: P=0.011; single treatment of Bix, P=0.045). The results of the present study suggest that accumulation of low-dose Bix enhanced the migration and metastatic potential of glioblastoma cells by regulating EMT-associated gene expression, which may be the cause of the altered properties of glioblastoma stem cells.
已知BIX01294（Bix）是一种常染色质组蛋白赖氨酸N-甲基转移酶2抑制剂，用Bix处理可抑制癌细胞的存活和增殖。在本研究中，观察到低剂量Bix的序贯治疗显著增加了胶质母细胞瘤细胞的迁移和转移。结果表明，用低剂量Bix序贯处理的U251细胞在关键的上皮-间质转化（EMT）标志物，包括E-钙黏蛋白、N-钙黏蛋白、β-连环蛋白和锌指蛋白SNAI2中表现出诱导的特征性变化。值得注意的是，Bix的序贯治疗还增加了癌症干细胞相关标志物的表达，包括性别决定区Y盒2、八聚体结合转录因子4和分化簇133。与对照细胞相比，用Bix序贯处理的细胞中神经球形成显著增强（对照：P=0.011；单次Bix处理，P=0.045）。本研究结果表明，低剂量Bix的积累通过调节EMT相关基因表达增强了胶质母细胞瘤细胞的迁移和转移潜能，这可能是胶质母细胞瘤干细胞特性改变的原因。
