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FLI1 mediates the selective expression of hypoxia-inducible factor 1 target genes in endothelial cells under hypoxic conditions.

ABSTRACT: 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% O₂ (normoxia) or 1% O₂ (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-1α 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-1α 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.

SUBMITTER: Zeng G

PROVIDER: S-EPMC8329784 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AIMS/INTRODUCTION:Given the high prevalence of diabetes and burn injuries worldwide, it is essential to dissect the underlying mechanism of delayed burn wound healing in diabetes patients, especially the high glucose-induced hypoxia-inducible factor 1 (HIF-1)-mediated transcription defects. MATERIALS AND METHODS:Human umbilical vein endothelial cells were cultured with low or high concentrations of glucose. HIF-1?-induced vascular endothelial growth factor (VEGF) transcription was measured by luciferase assay. Immunofluorescence staining was carried out to visualize cyclic adenosine monophosphate response element binding protein (CREB) localization. Immunoprecipitation was carried out to characterize the association between HIF-1?/p300/CREB. To test whether p300, CREB or p300+CREB co-overexpression was sufficient to rescue the HIF-1-mediated transcription defect after high glucose exposure, p300, CREB or p300+CREB co-overexpression were engineered, and VEGF expression was quantified. Finally, in vitro angiogenesis assay was carried out to test whether the high glucose-induced angiogenesis defect is rescuable by p300 and CREB co-overexpression. RESULTS:Chronic high glucose treatment resulted in impaired HIF-1-induced VEGF transcription and CREB exclusion from the nucleus. P300 or CREB overexpression alone cannot rescue high glucose-induced HIF-1? transcription defects. In contrast, co-overexpression of p300 and CREB dramatically ameliorated high glucose-induced impairment of HIF-1-mediated VEGF transcription, as well as in vitro angiogenesis. Finally, we showed that co-overexpression of p300 and CREB rectifies the dissociation of HIF-1?-p300-CREB protein complex in chronic high glucose-treated cells. CONCLUSION:Both p300 and CREB are required for the function integrity of HIF-1? transcription machinery and subsequent angiogenesis, suggesting future studies to improve burn wound healing might be directed to optimization of the interaction between p300, CREB and HIF-1?.

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FLI1 mediates the selective expression of hypoxia-inducible factor 1 target genes in endothelial cells under hypoxic conditions.

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