IDH1-R132H Suppresses Glioblastoma Malignancy through FAT1-ROS-HIF-1α Signaling.

Abstract

Glioblastoma (GBM) is one of the most deadly primary malignant brain tumors in adults. R132H mutation of isocitrate dehydrogenase 1 (IDH1) predicts a better prognosis of GBM. IDH1-R132H is associated with increased hypoxia-inducible factor-1α (HIF-1α) expression in GBM tumors. However, the molecular mechanism underlying IDH1-R132H-HIF-1α signaling in GBM is still unclear. We aimed to investigate the molecular pathway of IDH1-R132H-HIF-1α in the regulation of GBM. U87 and U251 GBM cells and xenograft tumor mice were used. We found that overexpression of IDH1-R132H decreased cell proliferation, increased apoptosis, decreased migration and invasion, enhanced temozolomide (TMZ)-induced cytotoxicity, and reduced tumor growth in xenograft mice. Overexpression of IDH1-R132H increased the expression of HIF-1α and downregulation of HIF-1α suppressed IDH1-R132H-induced effect on GBM. Reactive oxygen species (ROS) level was increased by IDH1-R132H over expression and the use of antioxidant inhibited IDH1-R132H-induced increase of HIF-1α expression. FAT Atypical Cadherin 1 (FAT1) expression was increased by IDH1-R132H over expression. Knockdown of FAT1 blocked IDH1-R132H-induced reduction of tumor growth in xenograft mice. Down regulation of FAT1 decreased HIF-1α expression and inhibited IDH1-R132H-induced increase of ROS level. Our findings provide new insights into IDH1-R132H-regulated downstream signaling in GBM and highlight the importance of IDH1-R132H-FAT1-ROS-HIF-1α signaling pathway in potential therapeutic intervention of GBM.