Valproic acid induces functional heat-shock protein 70 via Class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation.
Neuroprotective properties of the mood stabilizer valproic acid (VPA) are implicated in its therapeutic efficacy. Heat-shock protein 70 (HSP70) is a molecular chaperone, neuroprotective and anti-inflammatory agent. This study aimed to investigate underlying mechanisms and functional significance of HSP70 induction by VPA in rat cortical neurons. VPA treatment markedly up-regulated HSP70 protein levels, and this was accompanied by increased HSP70 mRNA levels and promoter hyperacetylation and activity. Other HDAC inhibitors--sodium butyrate, trichostatin A, and Class I HDAC-specific inhibitors MS-275 and apicidin, --all mimicked the ability of VPA to induce HSP70. Pre-treatment with phosphatidylinositol 3-kinase inhibitors or an Akt inhibitor attenuated HSP70 induction by VPA and other HDAC inhibitors. VPA treatment increased Sp1 acetylation, and a Sp1 inhibitor, mithramycin, abolished the induction of HSP70 by HDAC inhibitors. Moreover, VPA promoted the association of Sp1 with the histone acetyltransferases p300 and recruitment of p300 to the HSP70 promoter. Further, VPA-induced neuroprotection against glutamate excitotoxicity was prevented by blocking HSP70 induction. Taken together, the data suggest that the phosphatidylinositol 3-kinase/Akt pathway and Sp1 are likely involved in HSP70 induction by HDAC inhibitors, and induction of HSP70 by VPA in cortical neurons may contribute to its neuroprotective and therapeutic effects.
Marinova
Zoya
Z
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
Ren
Ming
M
Wendland
Jens R
JR
Leng
Yan
Y
Liang
Min-Huei
MH
Yasuda
Shigeru
S
Leeds
Peter
P
Chuang
De-Maw
DM
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D007136:Immunoglobulins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D007136:Immunoglobulins; C090698:SP1 antigen; D013778:Tetrazolium Salts; D013844:Thiazoles; D014635:Valproic Acid; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; C022616:thiazolyl blue; C004651:dipropylacetamide