PPARα, a predictor of patient survival in glioma, inhibits cell growth through the E2F1/miR-19a feedback loop

Nuclear receptors such as peroxisome proliferator-activated receptor a (PPAR alpha) are potential therapeutic targets. In this study, we found that PPAR alpha expression was lower in high grade gliomas and PPAR alpha was an independent prognostic factor in GBM patients. PPAR alpha agonism or overexpression inhibited glioma cell proliferation, invasion, and aerobic glycolysis as well as suppressed glioma growth in an orthotopic model. Bioinformatic analysis and luciferase reporter assays showed that miR-19a decreased PPAR alpha expression. E2F1 knockdown up-regulated PPAR alpha and inhibited cell proliferation, invasion, and aerobic glycolysis, but this activity was blocked by miR-19a. Knockdown of E2F1 decreased miR-19a by inhibiting the miR-19a promoter. Moreover, PPAR alpha repressed E2F1 via the p21 pathwayby modulating the transcriptional complexes containing E2F1 and pRB proteins. These results suggest that the E2F1/miR19a/PPAR alpha feedback loop is critical for glioma progression.