PMID:19158084

Citation	Kekatpure, VD, Dannenberg, AJ and Subbaramaiah, K (2009) HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling. J. Biol. Chem. 284:7436-45
Abstract	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.
Links	PubMed PMC2658039 Online version:10.1074/jbc.M808999200
Keywords	Acetylation/drug effects; Aryl Hydrocarbon Hydroxylases; Cell Line, Tumor; Cytochrome P-450 CYP1A1/biosynthesis; Cytochrome P-450 CYP1A1/genetics; Cytochrome P-450 Enzyme System/biosynthesis; Cytochrome P-450 Enzyme System/genetics; Dioxins/pharmacology; Environmental Pollutants/pharmacology; Enzyme Activation/drug effects; Enzyme Inhibitors/pharmacology; HSP90 Heat-Shock Proteins/genetics; HSP90 Heat-Shock Proteins/metabolism; Histone Deacetylase Inhibitors; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; Humans; Hydroxamic Acids/pharmacology; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Intramolecular Oxidoreductases/genetics; Intramolecular Oxidoreductases/metabolism; Mutation; Polycyclic Hydrocarbons, Aromatic/pharmacology; Receptors, Aryl Hydrocarbon/agonists; Receptors, Aryl Hydrocarbon/genetics; Receptors, Aryl Hydrocarbon/metabolism; Signal Transduction
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:HDAC6	involved_in	GO:0009636: response to toxic substance	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:HDAC6	involved_in	GO:0010033: response to organic substance	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:HDAC6	involved_in	GO:0009967: positive regulation of signal transduction	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:HDAC6	involved_in	GO:0010469: regulation of signaling receptor activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:HDAC6	involved_in	GO:0070846: Hsp90 deacetylation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:HDAC6	involved_in	GO:0090035: positive regulation of chaperone-mediated protein complex assembly	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

See Help:References for how to manage references in GONUTS.