We showed that CDK5 regulates glioma tumorigenicity by promoting TRIM59 nuclear translocation via PIN1/importin α5 axis, leading to STAT3 signaling activation, and demonstrate that CDK5 mediates EGFR-stimulated STAT3 signaling through activation of the TRIM59/mH2A1 axis in GBM. The gene discussed is CDK5; the disease is central nervous system cancer.