Phosphatidylinositol 4-kinase α suppresses glioblastoma progression by inactivating YAP and PI3K/Akt signaling

Glioblastoma multiforme (GBM) is one of the most malignant tumors of the central nervous system and is characterized by altered lipid metabolism. Notably, phosphatidylinositol (PI) metabolism is reprogrammed in GBM; however, its role and mechanism in GBM remain unclear. In this study, we found that phosphatidylinositol 4-kinase α (PI4Kα) (a subtype of PI4Ks) was downregulated in both low- and high-grade glioma tissues from clinical patients. Overexpressing the C terminus (1199-2102 amino acids) of PI4Kα, containing its catalytic domain (hereafter referred to as PI4Kα-CD for simplicity), in U251 and C6 cells (GBM cell lines), could significantly inhibit their proliferation and migration, whereas PI4Kα knockdown promoted their growth and migration. Mechanistically, PI4Kα inactivated YAP signaling by enhancing p-YAP (a major downstream effector of the Hippo pathway) and reducing the nuclear translocation of YAP, as well as suppressing PI3K/Akt signaling. YAP activation significantly restored the PI4Kα-CD overexpression-induced inhibitory effects on GBM growth. Finally, the growth of intracranially orthotopically transplanted PI4Kα-CD-overexpressing GBM cells in C57BL/6 mice was also suppressed through YAP signaling. Overall, these results reveal an unrecognized function of PI4Kα as a repressor in GBM progression through inactivation of YAP and PI3K/Akt signaling, thus providing a potential target for GBM treatment.