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Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha
Journal article   Open access   Peer reviewed

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

Donna M Fath, Xianguo Kong, Dongming Liang, Zhao Lin, Andrew Chou, Yubao Jiang, Jie Fang, Jaime Caro and Nianli Sang
The Journal of biological chemistry, v 281(19), pp 13612-13619
12 May 2006
DOI: https://doi.org/10.1074/jbc.M600456200
PMID: 16543236
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1074/jbc.M600456200View
Published, Version of Record (VoR) Open

Abstract

Basic Helix-Loop-Helix Transcription Factors - genetics Hypoxia-Inducible Factor 1, alpha Subunit - genetics Down-Regulation Humans Transcriptional Activation Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Protein p53 - genetics Gene Expression Regulation, Enzymologic Basic Helix-Loop-Helix Transcription Factors - metabolism Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Cell Line, Tumor Protein Binding Histone Deacetylase Inhibitors Von Hippel-Lindau Tumor Suppressor Protein - genetics Binding Sites Von Hippel-Lindau Tumor Suppressor Protein - metabolism
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-alphaCAD). 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-alphaCAD. 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-1alpha.p300 complex in vivo. In vitro acetylation analysis reveals that the p300CH1 region, but not HIF-alphaCAD, is susceptible to acetylation. Taken together, our data demonstrate that a deacetylase activity is indispensable for the transactivation potential of HIF-alphaCAD 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-1alpha and HIF-2alpha 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.

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Web of Science research areas
Biochemistry & Molecular Biology
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