Regulation of the HIF-1α stability by histone deacetylases

Histone deacetylase inhibitors (HDACIs) are currently in clinical trials partly due to their potent antiangiogenic effects. However, the detailed mechanism of their action is unclear. Here, we observed that several HDACIs (TSA, SB, Apicidin, and VPA) dramatically decreased HIF-1 alpha protein level and transcriptional activity of HIF-1 in human and mouse tumor cell lines. Furthermore, class I HDACs, HDAC1 and 3 enhanced HIF-1 alpha 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-1 alpha. Collectively, these results suggest that HDAC1 and 3 are considered as a positive regulator of HIF-1 alpha stability via direct interaction and may play an important role in HIF-1-induced tumor angiogenesis.