R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/β-catenin signaling.

Abstract

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene commonly occur in gliomas. Remarkably, the R132H mutation in IDH1 (IDH1-R132H) is associated with better prognosis and increased survival than patients lacking this mutation. The molecular mechanism underlying this phenomenon is largely unknown. In this study, we investigated potential cross-talk between IDH1-R132H and Wnt/β-catenin signaling in regulating the cellular properties of human glioma. Although aberrant nuclear accumulation of β-catenin is linked to the malignant progression of gliomas, its association with IDH1 remains unknown. We identified an inverse correlation between IDH1-R132H and the expression and activity of β-catenin in human gliomas. In addition, overexpression of IDH1-R132H in glioblastoma cell lines U87 and U251 led to reduced cell proliferation, migration and invasion, accompanied by increased apoptosis. At the molecular level, we detected a significant reduction in the expression, nuclear accumulation and activity of β-catenin following overexpression of IDH1-R132H. A microarray-based comparison of gene expression indicated that several mediators, effectors and targets of Wnt/β-catenin signaling are downregulated, while negative regulators are upregulated in IDH1-R132H gliomas. Further, overexpression of β-catenin in IDH1-R132H glioma cells restored the cellular phenotype induced by this mutation. Specifically, β-catenin abrogated the decrease in proliferation, invasion and migration, and the increase in apoptosis, triggered by overexpression of IDH1-R132H. Finally, we demonstrate that xenografts of IDH1-R132H overexpressing U87 cells can significantly decrease the growth of tumors in vivo. Altogether, our results strongly suggest that the R132H mutation in IDH1 serves a tumor suppressor function in human glioma by negatively regulating Wnt/β-catenin signaling.

• Authors: Daming Cui, Jie Ren, Jinlong Shi, Lijing Feng, Ke Wang, Tao Zeng, Yi Jin, Liang Gao
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 73 Pg. 72-81 (Apr 2016) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 26860959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• beta Catenin
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Brain Neoplasms (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics, physiology)
• Cell Survival (drug effects)
• Glioblastoma (genetics)
• Glioma (genetics, metabolism)
• Humans
• In Vitro Techniques
• Isocitrate Dehydrogenase (genetics)
• Mutation
• Wnt Signaling Pathway (genetics)
• beta Catenin (metabolism)