Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha

作者：Fath DM; Kong XG; Liang DM; Lin Z; Chou A; Jiang YB; Fang J; Caro J; Sang NL^*

来源：Journal of Biological Chemistry, 2006, 281(19): 13612-13619.

DOI：10.1074/jbc.M600456200

Hypoxia- inducible factors (HIFs) are heterodimeric transcription factors regulating the oxygen supply, glucose metabolism, and angiogenesis. HIF function requires the recruitment of p300/CREB-binding protein, two coactivators with histone acetyltransferase activity, by the C-terminal transactivation domain of HIF-alpha (HIF-alpha CAD). Histone deacetylase inhibitors (HDAIs) induce differentiation or apoptosis and repress tumor growth and angiogenesis, hence being explored intensively as anti-cancer agents. Using combined pharmacological, biochemical, and genetic approaches, here we show that HDAIs repress the transactivation potential of HIF-alpha CAD. This repression is independent of the function of tumor suppressors von Hippel-Lindau or p53 or the degradation of HIF-alpha. We also demonstrate the sufficiency of low concentrations of HDAIs in repression of HIF target genes in tumor cells. We further show that HDAIs induce hyperacetylation of p300 and repress the HIF-1 alpha p300 complex in vivo. In vitro acetylation analysis reveals that the p300CH1 region, but not HIF-alpha CAD, is susceptible to acetylation. Taken together, our data demonstrate that a deacetylase activity is indispensable for the transactivation potential of HIF-CAD and support a model that acetylation regulates HIF function by targeting HIF-alpha p300 complex, not by direct acetylating HIF-alpha. The demonstration that HDAIs repress both HIF-1 alpha and HIF-2 alpha transactivation potential independently of von Hippel-Lindau tumor suppressor and p53 function indicates that HDAIs may have biological effects in a broad range of tissues in addition to tumors.

• 出版日期2006-5-12