Regulation of the HIF-1alpha stability by histone deacetylases.
Histone deacetylase inhibitors (HDACIs) are currently in clinical trials partly due to their potent anti-angiogenic effects. However, the detailed mechanism of their action is unclear. Here, we observed that several HDACIs (TSA, SB, Apicidin, and VPA) dramatically decreased HIF-1alpha protein level and transcriptional activity of HIF-1 in human and mouse tumor cell lines. Furthermore, class I HDACs, HDAC1 and 3 enhanced HIF-1alpha stability and HIF-1 transactivation function in hypoxic conditions. In addition, immunoprecipitation and in vitro binding assays revealed that HDAC1 and 3 directly bind to the oxygen-dependent degradation domain of HIF-1alpha. Collectively, these results suggest that HDAC1 and 3 are considered as a positive regulator of HIF-1alpha stability via direct interaction and may play an important role in HIF-1-induced tumor angiogenesis.
Kim
Se-Hee
SH
NeuroVascular Coordination Research Center, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Jeong
Joo-Won
JW
Park
Jeong Ae
JA
Lee
Ji-Won
JW
Seo
Ji Hae
JH
Jung
Bo-Kyung
BK
Bae
Moon-Kyoung
MK
Kim
Kyu-Won
KW
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010456:Peptides, Cyclic; C102351:apicidin; C012589:trichostatin A; D014635:Valproic Acid; D006655:Histone Deacetylases