Regulation of the HIF-1α 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-la protein level and transcriptional activity of HIF-1 in human and mouse tumor cell lines. Furthermore, class I HDACs, HDAC1 and 3 enhanced HIF-la 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-la. Collectively, these results suggest that HDAC1 and 3 are considered as a positive regulator of HIF-la stability via direct interaction and may play an important role in HIF-1-induced tumor angiogenesis.