title: Chemopreventive and chemotherapeutic effect of a novel histone deacetylase inhibitor, by specificity protein 1 in MDA-MB-231 human breast cancer cells.
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.
authors.affiliation: aDepartment of Oral Pathology, School of Dentistry, Institute of Oral Bioscience, Chonbuk National University, Jeonju bDepartment of Biotechnology cDepartment of Biomedical Sciences (WCU program), TRCP, Yonsei University dJE UK Laboratory of Molecular Cancer Therapeutics, Institute for Cancer Research, College of Medicine, Yonsei University, Seoul eDepartment of Preventive Pharmacy, Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Ji-Ae
authors.initials: JA
authors.lastname: Shin
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Cho
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018890:Chemoprevention; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D004358:Drug Therapy; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D010456:Peptides, Cyclic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C555819:Ky-2 cyclic peptide; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D045304:Cytochromes c