We show that a histone deacetylase (HDAC) inhibitor apicidin increases the transcriptional activity of cyclin E gene, which results in accumulation of cyclin E mRNA and protein in a time- and close-dependent manner. Interestingly, apicidin induction of cyclin E gene is found to be mediated by Sp1- rather than E21F-bincling sites in the cyclin E promoter, as evidenced by the fact that specific inhibition of Sp1 leads to a decrease in apicidin activation of cyclin E promoter activity and protein expression, but mutation of E2F-binding sites of cyclin E promoter region fails to inhibit the ability of apicidin to activate cyclin E transcription. In addition, this transcriptional activation of cyclin E by apicidin is associated with historic hyperacetylation of cyclin E promoter region containing Sp1-binding sites. Our results demonstrate that regulation of historic modification by an HDAC inhibitor apicidin contributes to induction of cyclin E expression and this effect is Sp1-dependent. (c) 2006 Elsevier Inc. All rights reserved.