title: Histone hyperacetylation up-regulates protein kinase Cδ in dopaminergic neurons to induce cell death: relevance to epigenetic mechanisms of neurodegeneration in Parkinson disease.
abstract: The oxidative stress-sensitive protein kinase Cδ (PKCδ) has been implicated in dopaminergic neuronal cell death. However, little is known about the epigenetic mechanisms regulating PKCδ expression in neurons. Here, we report a novel mechanism by which the PKCδ gene can be regulated by histone acetylation. Treatment with histone deacetylase (HDAC) inhibitor sodium butyrate (NaBu) induced PKCδ expression in cultured neurons, brain slices, and animal models. Several other HDAC inhibitors also mimicked NaBu. The chromatin immunoprecipitation analysis revealed that hyperacetylation of histone H4 by NaBu is associated with the PKCδ promoter. Deletion analysis of the PKCδ promoter mapped the NaBu-responsive element to an 81-bp minimal promoter region. Detailed mutagenesis studies within this region revealed that four GC boxes conferred hyperacetylation-induced PKCδ promoter activation. Cotransfection experiments and Sp inhibitor studies demonstrated that Sp1, Sp3, and Sp4 regulated NaBu-induced PKCδ up-regulation. However, NaBu did not alter the DNA binding activities of Sp proteins or their expression. Interestingly, a one-hybrid analysis revealed that NaBu enhanced transcriptional activity of Sp1/Sp3. Overexpression of the p300/cAMP-response element-binding protein-binding protein (CBP) potentiated the NaBu-mediated transactivation potential of Sp1/Sp3, but expressing several HDACs attenuated this effect, suggesting that p300/CBP and HDACs act as coactivators or corepressors in histone acetylation-induced PKCδ up-regulation. Finally, using genetic and pharmacological approaches, we showed that NaBu up-regulation of PKCδ sensitizes neurons to cell death in a human dopaminergic cell model and brain slice cultures. Together, these results indicate that histone acetylation regulates PKCδ expression to augment nigrostriatal dopaminergic cell death, which could contribute to the progressive neuropathogenesis of Parkinson disease.
authors.affiliation: From the Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.affiliation: From the Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011.
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
authors.affiliation: From the Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011.
authors.forename: Dilshan S
authors.initials: DS
authors.lastname: Harischandra
authors.affiliation: From the Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011.
authors.forename: Naveen
authors.initials: N
authors.lastname: Kondru
authors.affiliation: From the Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011.
authors.forename: Anamitra
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: From the Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Panicker
authors.affiliation: From the Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011.
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.affiliation: the Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, and the Hines Veterans Affairs Medical Center, Hines, Illinois 60141.
authors.forename: Ajay
authors.initials: A
authors.lastname: Rana
authors.affiliation: From the Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011, akanthas@iastate.edu.
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000473:pathology; D020148:Butyric Acid / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000473:pathology*; D044127:Epigenesis, Genetic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051703:Sp Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D051703:Sp Transcription Factors; D020148:Butyric Acid; D050880:p300-CBP Transcription Factors; D051745:Protein Kinase C-delta
keywords: Epigenetics; Histone Acetylation; Histone Deacetylase Inhibitor (HDAC Inhibitor); Neurodegeneration; Oxidative Stress; PKCδ; Parkinson Disease