IDH1 mutation decreases the invasiveness of glioma by downregulating the expression and activity of TAZ

Abstract

Background and Aim: Gliomas carrying mutated isocitrate dehydrogenase 1 (IDH1) have an improved prognosis, but how this mutation improves survival is not known. In this study, we evaluated the correlation of expression of the gene transcriptional coactivator with PDZ-binding motif (TAZ) with IDH1 mutation in astrocytomas of different grades. Materials and Methods: We analyzed the expression of TAZ by immunohistochemistry in a cohort of 90 formalin-fixed paraffin-embedded human astrocytoma samples. A human glioblastoma cell line (U87) was transfected with mutated IDH1R132H; the expression and subcellular location of TAZ were analyzed by western blot assay, quantitative real-time polymerase chain reaction, and immunofluorescence staining. We detected activation of the Hippo signaling pathway by western blot. Octyl-2-hydroxyglutarate (Octyl-2-HG), an analog of 2-HG, was used to treat IDH1 wild-type U87 cells to determine its influence on the expression of TAZ. Cell viability assay, flow cytometry, Transwell migration assay, and scratch assay were used to analyze cell proliferation and invasive capacity. To verify that those changes were caused by the expression of TAZ, we did a rescue experiment by transfecting TAZ in the IDH1R132H cells. The study was approved by the Ethics Committee of Fudan University (approval No. 2016-Y013) on January 18, 2016. Results: TAZ expression was significantly lower in IDH1-mutated astrocytoma than the wild type in the same tumor grade. In IDH1-mutant cells, the nuclear TAZ location was decreased and the Hippo signaling pathway was activated as determined by TAZ phosphorylation and increased 14-3-3e expression. Treatment with Octyl-2-HG reduced the expression of TAZ. IDH1R132H cells showed decreased invasion proliferation compared with IDH1 wild-type cells. Overexpression of TAZ rescued cell migration and invasion capacity. Conclusion: In glioma, IDH1R132H mutation decreases TAZ expression and significantly reduces the invasive character of glioma cells.