Induction of GRP78 by valproic acid is dependent upon histone deacetylase inhibition.
Valproic (2-propylpentanoic) acid is a commonly used drug in the treatment of bipolar disorder and epilepsy. The molecular mechanism that underlies its clinical efficacy remains controversial and is complicated by the broad range of intracellular effects of valproic acid, including its ability to inhibit histone deacetylase (HDAC) and induce protein chaperone expression. Here we show that an established HDAC inhibitor, trichostatin A, promotes ER chaperone expression in HEK293 cells. Furthermore, we use chemical derivatives of valproic acid to show that the ability to promote GRP78 levels directly correlates with the induction of histone H4 hyperacetylation. These results suggest that exposure to valproic acid enhances chaperone expression by a mechanism that involves histone hyperacetylation.
Shi
Yuanyuan
Y
Henderson Research Centre, 711 Concession Street, Hamilton, Ont., Canada L8V 1C3.
Gerritsma
David
D
Bowes
Anna J
AJ
Capretta
Alfredo
A
Werstuck
Geoff H
GH
D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018832:Molecular Chaperones; D014635:Valproic Acid