A) Schematic of p300-TAD constructs and the assay system. B, C) p300-N-TAD and p300-C-TAD activity under normoxia and hypoxia after treatment with TSA (150-500 nM) (B) and Tubastatin A (15 μM) (C). Treatment with either TSA or Tubastatin decreased p300 transactivation potential under both normoxia and hypoxia. D) HRE-luciferase activity after transient overexpression of various HDAC isoforms. Overexpression of HDAC1 and HDAC3 irrespective of oxygen tension, and of HDAC4 and HDAC6 under hypoxia decreased HIF-1 activity. E) Proposed model of regulation of HIF-1α stability and activity by HDACs in NP cells. Multiple Class I and Class IIa HDACs promote HIF-1α stability in NP cells by regulating PHD2-HIF-1 interaction. In contrast, HDAC6, independently of regulating HIF-1α stability, promotes hypoxic induction of HIF-1 activity through positive effects on multiple cofactors including p300 and chaperone HSP90.