title: The histone deacetylase inhibitor trichostatin A induces neurite outgrowth in PC12 cells via the epigenetically regulated expression of the nur77 gene.
abstract: Histone deacetylase (HDAC) inhibitors induce histone acetylation and gene expression by changing local chromatin structures. They can thereby influence various cells to proliferate or differentiate. It has been reported that trichostatin A (TSA) or valproic acid (VPA) can induce the neuronal differentiation of mouse embryonic neural stem cells and rat cerebellar granule cells. It is unclear however which gene is responsible for the neuronal differentiation induced by HDAC inhibitors. In this study, we investigated the contribution of immediate early gene (IEG) nur77 to the neuronal differentiation induced by TSA. We report that TSA induces neurite outgrowth in PC12 cells, and C646, an inhibitor of HAT (histone acetyl transferase) (p300), prevents TSA-induced neurite formation. The acetylation of the Lys14 residue of histone H3, and mRNA and protein expression of nur77 gene were found to be stimulated after treatment with TSA, but not in the presence of C646. A knock-down of nur77 inhibits the neurite outgrowth induced by TSA. Furthermore, the ectopic expression of nur77 significantly elicits neurite formation in PC12 cells. These results suggest that the expression of nur77, which is up-regulated via the TSA-induced acetylation of Lys14 on histone H3, is essential for the neuronal differentiation in TSA-induced PC12 cells.
authors.affiliation: Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and Strategic Research Base, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka 564-8680, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Tomioka
authors.affiliation: Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and Strategic Research Base, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka 564-8680, Japan; Technical Research Laboratory, Kurabo Industries Ltd., Neyagawa, Osaka 572-0823, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Maruoka
authors.affiliation: Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and Strategic Research Base, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka 564-8680, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kawa
authors.affiliation: Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and Strategic Research Base, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka 564-8680, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Yamazoe
authors.affiliation: Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and Strategic Research Base, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka 564-8680, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Fujiki
authors.affiliation: Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and Strategic Research Base, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka 564-8680, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Shimoke
authors.affiliation: Laboratory of Neurobiology, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering and Strategic Research Base, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka 564-8680, Japan. Electronic address: v010032@kansai-u.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeuchi
mesh_terms: D000818:Animals; D002460:Cell Line; D044127:Epigenesis, Genetic / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D015854:Up-Regulation
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C012589:trichostatin A
keywords: Differentiation; HDAC inhibitor; Immediate early gene; Local chromatin structure; PC12 cell; nur77 gene