Forkhead Box M1 Is Essential for Nuclear Localization of Glioma-associated Oncogene Homolog 1 in Glioblastoma Multiforme Cells by Promoting Importin-7 Expression

The transcription factors glioma-associated oncogene homolog 1 (GLI1), a primary marker of Hedgehog pathway activation, and Forkhead box M1 (FOXM1) are aberrantly activated in a wide range of malignancies, including glioma. However, the mechanism of nuclear localization of GLI1 and whether FOXM1 regulates the Hedgehog signaling pathway are poorly understood. Here we found that FOXM1 promotes nuclear import of GLI1 in glioblastoma multiforme cells and thus increases the expression of its target genes. Conversely, knockdown of FOXM1 expression with FOXM1 siRNA abrogated its nuclear import and inhibited the expression of its target genes. Also, genetic deletion of FOXM1 in mouse embryonic fibroblasts abolished nuclear localization of GLI1. We observed that FOXM1 directly binds to the importin-7 (IPO7) promoter and increases its promoter activity. IPO7 interacted with GLI1, leading to enhanced nuclear import of GLI1. Depletion of IPO7 by IPO7 siRNA reduced nuclear accumulation of GLI1. In addition, FOXM1 induced nuclear import of GLI1 by promoting IPO7 expression. Moreover, the FOXM1/IPO7/GLI1 axis promoted cell proliferation, migration, and invasion in vitro. Finally, expression of FOXM1 was markedly correlated with that of GLI1 in human glioblastoma specimens. These data suggest that FOXM1 and GLI1 form a positive feedback loop that contributes to glioblastoma development. Furthermore, our study revealed a mechanism that controls nuclear import of GLI1 in glioblastoma multiforme cells.