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J Neurooncol. 2017 Jul;133(3):509-518. doi: 10.1007/s11060-017-2476-y. Epub 2017 Jun 22.

Epigenetically controlled Six3 expression regulates glioblastoma cell proliferation and invasion alongside modulating the activation levels of WNT pathway members.

Author information

1
Armed Police Hospital of Hunan Province, Changsha, 410008, Hunan, China.
2
Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China.
3
School of Basic Medicine, Central South University, Tongzipo Road 172, Changsha, 410013, China.
4
School of Basic Medicine, Central South University, Tongzipo Road 172, Changsha, 410013, China. zhangzuping@csu.edu.cn.

Abstract

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-β, β-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/β-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.

KEYWORDS:

Glioma; Invasion; Methylation; Proliferation; Six3; Wnt/β-catenin

PMID:
28643150
DOI:
10.1007/s11060-017-2476-y
[Indexed for MEDLINE]

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