Transcriptional up-regulation of FoxM1 in response to hypoxia is mediated by HIF-1.

The proliferation-specific Forkhead box M1 (FoxM1) transcription factor is overexpressed in cancer cells and acts as an important regulator of cancer cell growth and survival. Here, we show the molecular mechanisms by which hypoxia regulate FoxM1 expression in cancer cells. When cells were subjected to hypoxia (1% O2), the mRNA and protein levels of FoxM1 had a significant increase in cancer cells (HepG2, MCF-7, and HeLa). Such increase was due to the direct binding of hypoxia-inducible factor 1 (HIF-1) to the HIF-1 binding sites in the FoxM1 promoter. By deletion and mutation assays, we demonstrated that the HIF1-1 and HIF1-3/4 binding sites on the FoxM1 promoter were essential for transcriptional activation of FoxM1 by hypoxia. We also demonstrated that HIF-1alpha directly bound to the promoter of FoxM1 and the binding was specific, as revealed by HIF-1 binding/competition assay and chromatin immunoprecipitation assay. Consequently, the up-regulation of FoxM1 accelerated the growth of hypoxic cancer cells by decreasing nuclear levels of p21 and increasing expression of cyclin B1 and cyclin D1. These findings provide a new insight into how tumor cells overcome hypoxic stress and survive, and also disclose a new regulatory mechanism of FoxM1 expression in tumor cells.