FoxM1 drives ADAM17/EGFR activation loop to promote mesenchymal transition in glioblastoma

Abstract Mesenchymal transition (MES transition) is a hallmark of glioblastoma multiforme (GBM), however, the mechanism regulating the process remains to be elucidated. Here we report that FoxM1 drives ADAM17/EGFR activation loop to promote MES transition in GBM. Firstly, FoxM1 expression was positively associated with ADAM17 expression, and their expression was correlated with the mesenchymal features and overall patient survival of GBM. Overexpressing FoxM1 or ADAM17 increased the mesenchymal phenotype of glioma cells, which could be reversed by silencing FoxM1 or ADAM17. Importantly, FoxM1 bound to the ADAM17 promoter to transcriptionally upregulate its expression. Using gain- and loss-of-function studies, we showed that FoxM1/ADAM17 axis promoted the MES transition in glioma cells. Moreover, tissue microarray analysis and orthotopic xenograft model further confirmed that FoxM1/ADAM17 axis played key roles in malignancy of GBM. Mechanistically, FoxM1/ADAM17 axis activated the EGFR/AKT/GSK3β signaling pathway and ADAM17/EGFR/GSK3β axis could maintain FoxM1 stability in glioma cells. Taken together, our study demonstrated that FoxM1/ADAM17 feedback loop controlled the MES transition and regulated the progression of GBM, raising the possibility that deregulation of this loop might improve the durability of therapies in GBM.