Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-kappa B as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-kappa B activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-kappa B and the expression of its target genes, IL-8 and TNF-alpha. TNF-alpha expression by apicidin is induced at earlier time points than NF-kappa B activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappa B, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappa B, I kappa B alpha degradation or reporter gene activation by apicidin. However, this activation of NF-kappa B requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-kappa B seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappa B reporter gene activity. Collectively, our results suggest that activation of NF-kappa B signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin. (c) 2006 Elsevier Inc. All rights reserved.