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J. Biol. Chem., Vol. 276, Issue 45, 42084-42090, November 9, 2001

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Activation of p21^WAF1/Cip1 Transcription through Sp1 Sites by Histone Deacetylase Inhibitor Apicidin
INVOLVEMENT OF PROTEIN KINASE C^*

Jeung-Whan Han^§, Seong Hoon Ahn^§, Yong Kee Kim, Gyu-Un Bae, Jong Woo Yoon, Sungyoul Hong^¶, Hoi Young Lee, Yin-Won Lee^**, and Hyang-Woo Lee

From the  Department of Biochemistry and Molecular Biology, College of Pharmacy and the ^¶ Department of Genetic Engineering, College of Life Science and Natural Resources, Sungkyunkwan University, Suwon 440-746, the  Department of Pharmacology, College of Medicine, Konyang University, Nonsan 320-711, and the ^** School of Agricultural Biotechnology, Seoul National University, Suwon 441-744, Korea

We previously reported that apicidin, a novel histone deacetylase inhibitor, inhibited the proliferation of tumor cells via induction of p21^WAF1/Cip1. In this study, we determined the molecular mechanisms by which apicidin induced the p21^WAF1/Cip1 gene expression in HeLa cells. Apicidin induced p21^WAF1/Cip1 mRNA independent of the de novo protein synthesis and activated the p21^WAF1/Cip1 promoter through Sp1-3 site located at 82 and 77 relative to the transcription start site. This transcriptional activation appears to be mediated by protein kinase C (PKC), because calphostin C, a PKC inhibitor, significantly attenuated the activation of p21^WAF1/Cip1 promoter via Sp1 sites, which was accompanied by a marked suppression of p21^WAF1/Cip1 mRNA and protein expression induced by apicidin. Consistent with the transcriptional activation of p21^WAF1/Cip1 promoter by apicidin, apicidin treatment led to the translocation of PKC from cytosolic to particulate fraction, which was reversed by pretreatment with calphostin C, indicating the involvement of PKC in the transcriptional activation of p21^WAF1/Cip1 via Sp1 sites by apicidin. However, the PKC-mediated transcriptional activation of p21^WAF1/Cip1 by apicidin appears to be independent of the histone hyperacetylation, because apicidin-induced histone hyperacetylation was not affected by calphostin C. Furthermore, a PKC activator, phorbol 12,13-dibutyrate, alone induced the transcriptional activation of p21^WAF1/Cip1 promoter, p21^WAF1/Cip1 mRNA, and protein expression without induction of the histone hyperacetylation, suggesting that the transcriptional activation of p21^WAF1/Cip1 by apicidin might have been mediated by a mechanism other than chromatin remodeling through the histone hyperacetylation. Taken together, these results suggest that the PKC signaling pathway plays a pivotal role in the transcriptional activation of the p21^WAF1/Cip1 gene by apicidin.

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