Histone demethylase KDM6B inhibitor GSK-J4 sensitizes glioma cells to tyrosine kinase inhibitor anlotinib in vitro by reducing PDGFRA expression

This study investigated the pharmacological effects and potential mechanisms of the tyrosine kinase inhibitor anlotinib and the histone lysine demethylase 6B (KDM6B) inhibitor GSK-J4 on glioma cells. Brain pathological samples were analyzed with immunohistochemistry. The glioma cells U87MG and U251, and brain endothelial cell hCMEC/D3 were used in this study. Cell proliferation and migration were determined with CCK8 and scratch assays. The mRNA expressions of platelet derived growth factor receptor alpha ( PDGFRA ), PDGFR beta ( PDGFRB ) and KDM6B were detected with RT-qPCR. The protein levels of total PDGFRA and phosphorylated PDGFRA (p-PDGFRA) were measured with western blotting. The protein levels of total PDGFRA, p-PDGFRA and KDM6B were significantly elevated in malignant glioma tissues relative to control brain tissues. In vitro experiments demonstrated that anlotinib effectively inhibited glioma cell proliferation and migration, while GSK-J4 increased its inhibitory activity. The combination of two inhibitors showed no additional cytotoxicity toward brain endothelial cells. Further studies elucidated that the anlotinib primarily functions as a PDGFRA kinase inhibitor, whereas GSK-J4 exerts its effects through transcriptional repression of PDGFRA gene expression. The combination of anlotinib and GSK-J4 achieves dual inhibition of PDGFRA at both transcriptional and post-translational levels, representing a promising therapeutic strategy for glioma patients.