Depression of histone acetylation by alkylating antitumor agents: significance for antitumor activity and possible biological consequences

Abstract

Treatment of Ehrlich ascites tumor cells with the alkylating antitumor agents triaziquonum, N-mustard and cyclophosphamide leads to a reduction in the posttranslational incorporation of 3H-acetate into histones and the extent of histone acetylation in Ehrlich ascites tumor cells. All core histones are affected. The depression of histone acetylation is not the result of a decrease in acetyl-CoA. Evidence is presented for an activation of histone deacetylase by alkylating agents. A reduction of histone deacetylation is observed after exposure to all concentrations of alkylating agents which inhibit cell proliferation. In order to evaluate the biological consequences of a reduction of histone acetylation, the extent of acetylation was modulated by either chemical acetylation or treatment with butyrate. In all cases an increase in histone acetylation leads to an enhancement of the rate of transcription. In accord with previous reports from our laboratory (1), it is concluded that the reduction of histone acetylation affects RNA synthesis. It is emphasized, however, that besides a regulation of transcription, histone acetylation may be involved in other cell functions. Thus, the complete biological consequences of the reduction of histone acetylation remain to be elucidated. In view of the antitumor activity of the alkylating agents it seems noteworthy that hepatoma AS30D cells are characterized by a remarkably higher extent of histone H4-acetylation compared to normal, adult, fetal, or regenerating liver.