title: Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability.
abstract: Histone deacetylases (HDACs) are critical in the control of gene expression, and dysregulation of their activity has been implicated in a broad range of diseases, including cancer, cardiovascular, and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. Although it has also been suggested that HDACi with increased isozyme selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here, we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi vorinostat and trichostatin-A. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histone acetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that determining how the selective and kinetic inhibition properties of HDACi affect cell function will help to evaluate their therapeutic utility.
authors.affiliation: From the Departments of Neuroscience.
authors.forename: Benjamin E L
authors.initials: BE
authors.lastname: Lauffer
authors.forename: Robert
authors.initials: R
authors.lastname: Mintzer
authors.forename: Rina
authors.initials: R
authors.lastname: Fong
authors.forename: Susmith
authors.initials: S
authors.lastname: Mukund
authors.forename: Christine
authors.initials: C
authors.lastname: Tam
authors.forename: Inna
authors.initials: I
authors.lastname: Zilberleyb
authors.forename: Birgit
authors.initials: B
authors.lastname: Flicke
authors.forename: Allegra
authors.initials: A
authors.lastname: Ritscher
authors.forename: Grazyna
authors.initials: G
authors.lastname: Fedorowicz
authors.forename: Roxanne
authors.initials: R
authors.lastname: Vallero
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Lars
authors.initials: L
authors.lastname: Neumann
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Koth
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lupardus
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Kaminker
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Heise
authors.forename: Pascal
authors.initials: P
authors.lastname: Steiner
mesh_terms: D000107:Acetylation; D001549:Benzamides / Q000737:chemistry; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006657:Histones / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007700:Kinetics; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D014158:Transcription, Genetic; D000077337:Vorinostat
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011725:Pyridines; C118739:entinostat; C012589:trichostatin A; D000077337:Vorinostat
keywords: Binding Kinetics; Cell Cycle; Cell Death; Crystallography; Gene Expression; Histone Deacetylase; Histone Deacetylase Inhibitors; Histone Modification
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