FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells.
We previously found that FoxM1B is overexpressed in human glioblastomas and that forced FoxM1B expression in anaplastic astrocytoma cells leads to the formation of highly angiogenic glioblastoma in nude mice. However, the molecular mechanisms by which FoxM1B enhances glioma angiogenesis are currently unknown. In this study, we found that vascular endothelial growth factor (VEGF) is a direct transcriptional target of FoxM1B. FoxM1B overexpression increased VEGF expression, whereas blockade of FoxM1 expression suppressed VEGF expression in glioma cells. Transfection of FoxM1 into glioma cells directly activated the VEGF promoter, and inhibition of FoxM1 expression by FoxM1 siRNA suppressed VEGF promoter activation. We identified two FoxM1-binding sites in the VEGF promoter that specifically bound to the FoxM1 protein. Mutation of these FoxM1-binding sites significantly attenuated VEGF promoter activity. Furthermore, FoxM1 overexpression increased and inhibition of FoxM1 expression suppressed the angiogenic ability of glioma cells. Finally, an immunohistochemical analysis of 59 human glioblastoma specimens also showed a significant correlation between FoxM1 overexpression and elevated VEGF expression. Our findings provide both clinical and mechanistic evidence that FoxM1 contributes to glioma progression by enhancing VEGF gene transcription and thus tumor angiogenesis.
Zhang
Yujian
Y
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Zhang
Nu
N
Dai
Bingbing
B
Liu
Mingguang
M
Sawaya
Raymond
R
Xie
Keping
K
Huang
Suyun
S
D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D005910:Glioma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D017931:DNA Primers; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D042461:Vascular Endothelial Growth Factor A