Chemopreventive and chemotherapeutic effect of a novel histone deacetylase inhibitor, by specificity protein 1 in MDA-MB-231 human breast cancer cells

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Abstract

Histone deacetylase inhibitors (HDACi) have been reported to have potent chemopreventive activity because of their effects on the inhibition of cell growth and apoptosis in human cancer cell lines. In the present study, we investigated the apoptotic effect of a novel HDACi, Ky2, and its molecular mechanism in MDA-MB-231 human breast cancer cells in vitro. The chemopreventive effects of Ky2 in MDA-MB-231 cells were evaluated using the MTS assay, anchorage-independent cell transformation assay, DAPI staining, western blot analysis, reverse transcriptase-PCR, and small interfering RNA. Ky2 enhanced histone acetylation and decreased cell viability. Ky2 induced apoptosis evidenced by nuclear condensation and fragmentation, the accumulation of sub-G1 phase, and caspase-dependent PARP cleavage. In addition, Ky2 released cytochrome c from mitochondria to cytosol through the regulation of mitochondria-related proteins (Bid, Bim, and Bcl-xL). Ky2 markedly decreased the level of Sp1 protein expression through both the decrease of Sp1 mRNA level and proteasome-dependent protein degradation. Interestingly, the apoptotic effect of Ky2 is more potent than SAHA, a well-known HDACi. Furthermore, the knockdown of Sp1 protein by Sp1-specific inhibitor, mithramycin A, and siRNA resulted in the alteration of truncated Bid and Bim to induce apoptosis. Furthermore, Ky2 significantly decreased TPA-induced or EGF-induced neoplastic cell transformation in JB6 cells. Our results suggest that Ky2 may be a potential chemopreventive and chemotherapeutic agent by modulating Sp1 in human breast cancer cells.

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