Journal
CELL CYCLE
Volume 10, Issue 5, Pages 760-766Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.5.14827
Keywords
adherens junction; cancer; DNA binding; epithelial-to-mesenchymal transition (EMT); E-Cadherin; FOXM1; promoter; transactivation; transcription; tumorigenesis
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This study demonstrates for the first time that FOXM1c transactivates the murine E-cadherin promoter. It shows also that the purified DNA-binding domain of FOXM1c binds to the murine and human E-cadherin promoters in vitro, namely to a perfectly conserved FOXM1 site. Thus, this study identifies E-cadherin as a new direct FOXM1c target gene. This finding is surprising because E-cadherin is a tumor suppressor gene whereas FOXM1 is a proliferation-associated and tumorigenesis-promoting transcription factor. The transmembrane glycoprotein E-cadherin mediates cell-cell adhesion in adherens junctions. Its expression is frequently lost or reduced in human tumors, which correlates with poor prognosis. Downregulation of E-cadherin represents a central event in epithelial-to-mesenchymal transition. In contrast, FOXM1 contributes to oncogenic transformation and participates in tumor initiation and progression. It is overexpressed in many human cancers and a high FOXM1 level correlates with poor prognosis. FOXM1 stimulates cell proliferation and promotes cell cycle progression at the G(1)/S- and G(2)/M-transitions. The surprising finding that FOXM1c transactivates the promoter of the tumor suppressor gene E-cadherin points to a tumor-suppressive property of FOXM1. This view is supported by FOXM1's new tumor suppressor role as others reported that urethane-induced lung tumorigenesis is increased in mice with an endothelial cell-specific foxm1 deletion.
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