Fli1 Mediates The Selective Expression Of Hypoxia-Inducible Factor 1 Target Genes In Endothelial Cells Under Hypoxic Conditions

The selective expression of hypoxia-inducible factor (HIF) target genes in different physiological and pathological environments forms the basis for cellular adaptation to hypoxia in development and disease. Several E26 transformation-specific (ETS) transcription factors have been shown to specifically regulate the expression of a subset of HIF-2 target genes. However, it is unknown whether there are ETS factors that specifically regulate hypoxia-induced HIF-1 target genes. The present study was undertaken to explore whether friend leukemia integration 1 (FLI1), an ETS transcription factor, regulates the expression of HIF-1 target genes. To investigate this possibility, EA.hy926 cells were exposed to 20% O-2 (normoxia) or 1% O-2 (hypoxia). Western blotting, immunofluorescence staining, and RT-qPCR revealed that FLI1 mRNA and protein levels increased slightly and that the FLI1 protein co-localized with HIF-1 alpha in the nucleus under hypoxic conditions. Further analysis showed that, in the absence of FLI1, the hypoxia-mediated induction of HIF-1 target genes was selectively inhibited. The results from immunoprecipitation and luciferase reporter assays indicated that FLI1 cooperates with HIF-1 alpha and is required for the transcriptional activation of a subset of HIF-1 target genes with a core promoter region containing FBS in proximity to a functional hypoxia response element (HRE). Furthermore, ChIP analysis further confirmed the direct interaction between FLI1 and the promoter region of FLI1-dependent HIF-1 target genes under hypoxia. Together, this study demonstrates that FLI1 is involved in the transactivation of certain HIF-1 target genes in endothelial cells under hypoxic conditions.