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

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/beta-catenin signaling in regulating the cellular properties of human glioma. Although aberrant nuclear accumulation of beta-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 I3-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 p-catenin following overexpression of IDH1-R132H. A microarray-based comparison of gene expression indicated that several mediators, effectors and targets of Wnt/beta-catenin signaling are down regulated, while negative regulators are upregulated in IDH1-R132H gliomas. Further, overexpression of I3-catenin in IDH1-R132H glioma cells restored the cellular phenotype induced by this mutation. Specifically, P-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 Wntill-catenin signaling. (C) 2016 Elsevier Ltd. All rights reserved.