Expression of cyclin D3 through Sp1 sites by histone deacetylase inhibitors is mediated with protein kinase C-delta (PKC-delta) signal pathway.

The histone deacetylase (HDAC) inhibitors are an exciting new class of drugs that are targeted as anti-cancer agents. These compounds can induce growth arrest, apoptosis, and/or terminal differentiation in a variety of cancers. The inhibition of HDACs shifts toward hyper-acetylation, thereby driving transcriptional activation. In present study, HDAC inhibitor apicidin was used to elucidate the effect on expression of cell cycle related proteins and the molecular mechanism for transcriptional regulation of cyclin D3 in response to HDAC inhibitors in human colon cancer cells. We found that apicidin increases the transcriptional activity of cyclin D3 gene, which results in accumulation of cyclin D3 mRNA and protein. Apicidin-induced cyclin D3 expression is mediated by Sp1 sites within the cyclin D3 promoter. Apicidin-mediated cyclin D3 expression is attenuated by rottlerin, a specific protein kinase C-delta (PKC-delta) inhibitor, but not mitogen-activated protein kinases (MAPKs) inhibitors. Furthermore, suppression of PKC-delta expression by transfection with its siRNA prominently attenuated apicidin-induced cyclin D3 expression. These results indicate that the cyclin D3 induction caused by apicidin was associated with PKC-delta signaling pathway not MAPKs signaling pathways. Taken together, these results suggest that the activation of cyclin D3 transcription by HDAC inhibitor apicidin was mediated through Sp1 sites and pointed to the possible participation of PKC-delta.