In the present study, we showed that upregulation of HMGA1 and MYH9 in human gliomas is correlated with tumor progression, and knockdown of HMGA1 can inhibit the proliferation, migration, and invasion, as well as chemoresistance in glioma cells by stimulating MYH9-mediated ubiquitinated degradation of GSK-3β through PI3K/Akt/c-Jun pathway in vitro and in vivo. Here, HMGA1 is linked to central nervous system cancer.