HOTAIR-EZH2 Inhibitor AC1Q3QWB Upregulates CWF19L1 And Enhance Cell Cycle Inhibition Of CDK4/6 Inhibitor Palbociclib In Glioma

Background:Glioblastoma(GBM)is the most common primary tumor in the brain,the median survival time for GBM patients is only about 14 months,therefore,there is an urgent need for new and more effective strategies.Since cell cycle disorder is a key factor in tumor progression and immortalization,there is great potential for controlling cell cycle disorders in tumor cells in glioblastoma patients.We began to study a novel combination of AQB and palbociclib to evaluate its potential as a new therapeutic target.Method:Protein profiling analysis of the up-regulated protein expression after AQB treatment,TCGA,CGGA database analysis of CWF19L1 and glioma grade and prognostic correlation,analysis of histone modification of CWF19L1 promoter region by ChIP-qPCR experiment,we through plate cloning and CCK-8 Understand the proliferation of glioma cells,and double-stain flow cell cycle to detect the distribution of glioma cell cycle.Results:The combination of AQB and palbociclib inhibitors has a more pronounced suppression effect on the cell cycle,especially gliomas with high expression of HOTAIR and EZH2 and low expression of CWF19L1.our experimental results suggest that CWF19L1 is regulated by H3K27 ac,therefore,CWF19L1 can be significantly up-regulated by AQB and lead to degradation of CDK4/6,resulting in G1 arrest.The combination of AQB and CDK4/6 inhibitor palbociclib is more effective in inhibiting the growth of glioma than in the single drug,both in vivo and in vitro.Similarly,we found that both AQB and palbociclib can inhibit Wnt/?-catenin signaling,but the combined use of the two inhibitors has a stronger inhibitory effect on tumor metastasis.Conclusions:The combination of AQB and CDK4/6 inhibitor palbociclib has been found to have significant anti-tumor effects,which is likely to become a new strategy for glioma treatment.