In this study, we investigated the effect of dexamethasone on the expression of steroidogenic acute regulatory protein (StAR) and the acetylation of histone H3 in mouse Y-1 adrenocortical tumor cells. Treatment of Y-1 cells with increasing concentrations (0.001-50 microg/ml) of dexamethasone for 24 h suppressed 8-Br-cAMP (0.5 mM)-stimulated StAR mRNA and protein levels and progesterone production in a dose-dependent manner. Treatment of Y-1 cells with 8-Br-cAMP (0.5 mM) for 1-24 h resulted in a marked increase in StAR mRNA levels. This increase was associated with an increase in progesterone production. StAR mRNA was down-regulated by dexamethasone at times greater than 3 h. To evaluate dexamethasone effect on the endogenous StAR gene, chromatin immunoprecipitation assays were performed in combination with polymerase chain reaction. 8-Br-cAMP increased histone H3 acetylation within the proximal region of the StAR gene promoter and coincubation with dexamethasone blocked this effect. Dexamethasone had no effect on glucocorticoid receptor mRNA expression. These results demonstrate that dexamethasone repression of 8-Br-cAMP-stimulated StAR gene expression in Y-1 cells is accompanied by reductions in histone H3 acetylation associated with the StAR gene promoter.