Histone Deacetylase 7 Associates with Hypoxia-inducible Factor 1alpha and Increases Transcriptional Activity

Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that controls expression of genes responsive to low oxygen tension, including vascular endothelial growth factor (VEGF), erythropoietin, and glycolytic enzymes. The activity of HIF-1alpha is regulated by binding to the transcriptional co-activator cAMP-response element-binding protein-binding protein (CBP)/p300. Using the yeast two-hybrid screening system, we found that the inhibitory domain of HIF-1alpha strongly interacted with the C-terminal domain of histone deacetylase (HDAC) 7. The o-nitrophenyl beta-d-galactopyranoside assay revealed that regions containing amino acids 735-785 of HIF-1alpha and amino acids 669-952 of HDAC7 were minimum contact sites of the interaction. The binding of HDAC7 with HIF-1alpha was reproduced in HEK293 cells grown under normoxic and hypoxic conditions (2% O(2)). HDAC7 bound solely to HIF-1alpha among other HIF-alpha family members, including HIF-2alpha and HIF-3alpha, whereas HIF-1alpha only interacted with HDAC7 in the class II HDAC family. Although HDAC7 was localized dominantly in the cytoplasm at normal oxygen concentrations, HDAC7 co-translocated to the nucleus with HIF-1alpha under hypoxic conditions. In the nucleus, HDAC7 increased transcriptional activity of HIF-1alpha through the formation of a complex with HIF-1alpha, HDAC7, and p300. Taken together, these results indicate that HDAC7 is a novel transcriptional activator of HIF-1alpha