Epigenetically controlled Six3 expression regulates glioblastoma cell proliferation and invasion alongside modulating the activation levels of WNT pathway members
Epigenetically controlled Six3 expression regulates glioblastoma cell proliferation and invasion alongside modulating the activation levels of WNT pathway members
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DOI：
10.1007/s11060-017-2476-y
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发表时间：
2017-07-01
影响因子：
3.9
通讯作者：
Zhang, Zuping
中科院分区：
文献类型：
--
作者：
Zhang, Baoxin;Shen, Chenfu;Zhang, Zuping
胶质瘤是成人最常见的原发性脑肿瘤。Six 3是高度保守的sine oculis基因家族的同源基因，是眼和胎儿前脑发育过程中的重要转录调控因子。然而，关于Six 3在人类肿瘤发生中的作用知之甚少。本研究旨在探讨Six 3基因在胶质瘤中的甲基化及表达情况，揭示Six 3基因在胶质瘤中的功能及作用机制。结果显示，Six 3在人脑胶质瘤组织及人脑胶质瘤SHG-44、U251、SF 126和U373-MG细胞中的表达较正常组织明显下调。Six 3基因表达下调与其启动子甲基化有关。胶质瘤U251细胞缺乏内源性Six 3。去甲基化剂（5-aza-2 '-deoxycytidine）或Six 3的外源表达可恢复Six 3的产生，并导致胶质瘤U251细胞G1/S期转换、增殖和侵袭受到抑制，Wnt 1、p-GSK 3-beta、beta-catenin和cyclin D1的表达下调。然而，在具有相对较高的Six 3基线水平的SHG-44细胞中，Six 3的敲低导致相反的作用。这些结果表明，Six 3基因在胶质瘤中的沉默或丢失是由其启动子高甲基化诱导的，Six 3基因的下调有助于胶质瘤的增殖和侵袭。该过程参与了Wnt/beta-catenin通路的激活。Six 3基因在人脑胶质瘤的发生和发展中起抑制作用，有望成为人脑胶质瘤诊断和治疗的靶点。
Glioma is the most common primary brain tumor in adults. Six3 is a human homologue of the highly conserved sine oculis gene family and essential transcription regulatory factor in process of eye and fetal forebrain development. However, little is known about the role of Six3 in human tumorigenesis. The aim of this study is to investigate the methylation/expression of Six3 and reveal its function and action mechanism in glioma. Our results showed that Six3 was down-regulated in human glioma tissues and human glioma SHG-44, U251, SF126 and U373-MG cells compared with the normal tissues. And the down-regulation of Six3 was associated with the methylation of its promoter. Glioma U251 cells lacked endogenous Six3. Treatment with demethylating agent (5-aza-2'-deoxycytidine) or exogenous expression of Six3 restored Six3 production and resulted in suppression of cell cycle G1/S transition, proliferation and invasion and down-regulation of the expression of Wnt1, p-GSK3-beta, beta-catenin and cyclin D1 in glioma U251 cells. However, knockdown of Six3 in SHG-44 cells, which have relative higher baseline level of Six3, resulted in an opposite action. These results demonstrate that Six3 silence or loss in glioma is induced by its promoter hypermethylation and Six3 down-regulation contributes to proliferation and invasion of glioma. And this process is involved in activation of Wnt/beta-catenin pathway. Six3 play a suppressor role in the initiation and progression of human glioma and potentially serve as a target for the diagnosis and treatment of human glioma.