To determine the molecular mechanism of ZNF117-mediated GSC differentiation, we used a combination of cDNA array and chromatin immunoprecipitation sequencing (ChIP-seq) and found that ZNF117 regulates the Notch pathway through interaction of JAG2. Taken together, our results suggest that ZNF117 is a major regulator of GSC differentiation and can be targeted for GBM differentiation therapy to improve the clinical response to current treatment strategies. This evidence concerns the gene ZNF117 and glioblastoma.