Histone deacetylase7 regulates subcellular localization of HIF‐1α upon transition from hypoxia to normoxia (re‐oxygenation)

Hypoxia‐inducible factor‐1α (HIF‐1α) is a transcription factor, which plays an important role in physiological response to hypoxia by expression of various genes response to low oxygen tension, including vascular endothelial growth factor, erythropoietin, and glycolitic enzymes. We identified that the HIF‐1α‐interacting clone histone deacetylase (HDAC)7. HDAC7 translocates into the nucleus and enhances HIF‐1α transcription activity under hypoxia (Ref.1). The objective of this study was to determine the roles of HDAC7 in HIF‐1α degradation upon re‐oxygenation. We found that degradation of HIF‐1α was correlated with translocation of HDAC7 from the nucleus to the cytoplasm in the nucleus upon re‐oxygenation. Moreover the amino acids substitution mutations of nuclear export sequences (NES) in HDAC7 (NES mut HDAC7) blocked translocation of HDAC7 to the cytoplasm and stabilized HIF‐1α in the nucleus upon re‐oxygenation. Moreover NES mut HDAC7 bound HIF‐1α and suppressed ubqutination of HIF‐1α upon re‐oxygenation. The stabilized HIF‐1α by NES mut HDAC7 retained binding ability to p300 and delay of decrease in the amount of the VEGF RNA content. These results suggest that dissociation of HDAC7 from HIF‐1α‐HDAC7 complex and translocation of HDAC7 to the cytoplasm may lead to degradation of HIF‐1α and repress HIF‐1α transcriptional activity upon re‐oxygenation.