Activation of NF-κB by HDAC inhibitor apicidin through Sp1-dependent de novo protein synthesis: Its implication for resistance to apoptosis

Abstract

Histone deacetylase (HDAC) inhibitors are promising anti-cancer drugs, but these exert differential responses depending on the cell types. Here, we demonstrate a new mechanism for activation of nuclear factor-κB (NF-κB) by HDAC inhibitor apicidin and the role of NF-κB signaling pathway for mediating differential cellular responses, especially, apoptosis. Treatment of HeLa cells with apicidin increases transcriptional activity of NF-κB and its target gene IL-8 and cIAP-1 induction, which involves the activation of IKK-IκBα signaling pathway through Sp1-dependent de novo protein synthesis. In parallel, apicidin treatment leads to histone hyperacetylation in the IL-8 promoter region independent of NF-κB signaling pathway, which is not sufficient for full transcription of IL-8 gene. This NF-κB activation contributes to resistance of HeLa cells to apoptotic potential of apicidin. Collectively, our results suggest that activation of NF-κB signaling cascade functions as a critical modulator to determine cell fate on apoptosis in response to HDAC inhibitors. © 2006 Nature Publishing Group All rights reserved.