HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling.
The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic helix-loop-helix family of transcription factors, binds with high affinity to polycyclic aromatic hydrocarbons (PAH) and the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). Most of the biochemical, biological, and toxicological responses caused by exposure to PAHs and polychlorinated dioxins are mediated, at ... least in part, by the AhR. The AhR is a client protein of Hsp90, a molecular chaperone that can be reversibly acetylated with functional consequences. The main objective of this study was to determine whether modulating Hsp90 acetylation would affect ligand-mediated activation of AhR signaling. Trichostatin A and suberoylanilide hydroxamic acid, two broad spectrum HDAC inhibitors, blocked PAH and dioxin-mediated induction of CYP1A1 and CYP1B1 in cell lines derived from the human aerodigestive tract. Silencing HDAC6 or treatment with tubacin, a pharmacological inhibitor of HDAC6, also suppressed the induction of CYP1A1 and CYP1B1. Inhibiting HDAC6 led to hyperacetylation of Hsp90 and loss of complex formation with AhR, cochaperone p23, and XAP-2. Inactivation or silencing of HDAC6 also led to reduced binding of ligand to the AhR and decreased translocation of the AhR from cytosol to nucleus in response to ligand. Ligand-induced recruitment of the AhR to the CYP1A1 and CYP1B1 promoters was inhibited when HDAC6 was inactivated. Mutation analysis of Hsp90 Lys(294) shows that its acetylation status is a strong determinant of interactions with AhR and p23 in addition to ligand-mediated activation of AhR signaling. Collectively, these results show that HDAC6 activity regulates the acetylation of Hsp90, the ability of Hsp90 to chaperone the AhR, and the expression of AhR-dependent genes. Given the established link between activation of AhR signaling and xenobiotic metabolism, inhibitors of HDAC6 may alter drug or carcinogen metabolism.
Mesh Terms:
Acetylation, Cell Line, Tumor, Cytochrome P-450 CYP1A1, Cytochrome P-450 Enzyme System, Dioxins, Environmental Pollutants, Enzyme Activation, Enzyme Inhibitors, HSP90 Heat-Shock Proteins, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Intracellular Signaling Peptides and Proteins, Intramolecular Oxidoreductases, Mutation, Polycyclic Hydrocarbons, Aromatic, Receptors, Aryl Hydrocarbon, Signal Transduction
Acetylation, Cell Line, Tumor, Cytochrome P-450 CYP1A1, Cytochrome P-450 Enzyme System, Dioxins, Environmental Pollutants, Enzyme Activation, Enzyme Inhibitors, HSP90 Heat-Shock Proteins, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Intracellular Signaling Peptides and Proteins, Intramolecular Oxidoreductases, Mutation, Polycyclic Hydrocarbons, Aromatic, Receptors, Aryl Hydrocarbon, Signal Transduction
J. Biol. Chem.
Date: Mar. 20, 2009
PubMed ID: 19158084
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