Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha.
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.
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Donna M
DM
Fath
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Xianguo
X
Kong
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Dongming
D
Liang
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Zhao
Z
Lin
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Andrew
A
Chou
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Yubao
Y
Jiang
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Jie
J
Fang
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Jaime
J
Caro
Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107. Electronic address: nianli.sang@jefferson.edu.
Nianli
N
Sang
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D056572:Histone Deacetylase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human