The histone deacetylase inhibitor, Trichostatin A, induces G2/M phase arrest and apoptosis in YD-10B oral squamous carcinoma cells
ABSTRACT Histone acetylation is one of the key chromatin modifications that control gene transcription during development and tumorigenesis. Recently, it was reported that the histone deacetylase inhibitor, Trichostatin A (TSA), induces growth arrest and apoptosis in tumors. However, the molecular mechanisms responsible for its antitumor effects are not clear. The purpose of this study was to investigate the effect of TSA on human oral squamous carcinoma cells and to determine the mechanisms underlying the antitumor activity of TSA. MTT assays showed that TSA inhibited cell proliferation in YD-10B cells. TSA also effectively arrested cell cycle progression at the G2/M phase through the up-regulation of p21waf expression, down-regulation of Cyclin B1 and reduction of the inhibitory phophorylation of Cdc2. In addition, mitochondrial membrane destruction was induced by a 48 h TSA treatment. TSA also induced cytochrome c release and proteolytic activation of caspase 3 and caspase 7 in YD-10B cells. Taken together, these observations in YD-10B oral cancer cells reveal the potential value of TSA in inhibiting oral tumor growth.
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ABSTRACT: 15-Lipoxygenase-1 (15-Lox-1) is a key enzyme mediating oxidative metabolism of polyunsaturated fatty acids and has attracted considerable interest as a potential target for the induction of apoptosis in cancer cells. Knowledge of relationship between 15-Lox-1 and histone deacetylase inhibitors is lacking in the breast cancer. This study is aimed to investigate the role of Trichostatin A (TSA) and 13(S)-HODE, as a metabolite of 15-Lox-1, in the regulation of breast cancer cell growth. The cytotoxic effect of TSA, as a potent HDAC inhibitor, was measured using MTT assay. Annexin V-FITC and PI staining were performed to detect apoptosis and cell cycle distribution using Flow cytometry. The role of 15-Lox-1 in the regulation of cell growth was assessed by 15-Lox-1 inhibitor and the level of 15-Lox-1 metabolite was measured to determine 15-Lox activity after treatment by TSA. The results demonstrated that TSA induced cell growth inhibition via 15-Lox-1, in a dose- and time-dependent manner, and subsequently accompanied by the cell cycle arrest and induction of apoptosis. Moreover, growth inhibitory effect of TSA was associated with the elevation of 15-Lox-1 metabolite (13(S)-HODE). This study provided evidences that the inhibitory effect of TSA on the breast cancer cell growth occurs via the induction of 15-Lox-1 activity and 13(S)-HODE production. Our findings underline the possible role of 15-Lox-1/13(S)-HODE pathway as a promising molecular approach for the induction of apoptosis in breast cancer cells.Tumor Biology 10/2012; 34(1). DOI:10.1007/s13277-012-0544-7 · 3.61 Impact Factor
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ABSTRACT: Dysregulation of gene expression is a frequent occurrence in oral squamous cell carcinoma (OSCC). However, accumulating evidence suggests that in contrast to genetics, epigenetic modifications consisting of aberrant DNA methylation, histone modifications and altered expression of miRNAs induce OSCC tumorigenesis and perhaps play a more central role in the evolution and progression of this disease. The unifying theme among these three epigenetic mechanisms remains the same, which is aberrant regulation of gene expression. In this article, we provide a comprehensive review of the impact of epigenetics on oral tumorigenesis with a systematic report on aberrant DNA methylation, histone modifications and miRNA regulation in the pathogenesis of OSCC. We provide insights into recent studies on the prospect of biomarkers for early detection and indication of disease recurrence, and novel treatment modalities.Future Oncology 11/2012; 8(11):1407-1425. DOI:10.2217/fon.12.138 · 2.48 Impact Factor
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ABSTRACT: Oral hypoglycemic agent metformin is commonly used for treating type II diabetes; however, initial reports demonstrated that it could be used for suppressing tumor growth in vitro and in vivo. Moreover, novel potential anticancer drug histone deacetylase (HDAC) and inhibitor trichostatin A (TSA) have been extensively studied for inducing various malignancies growth inhibition, cell cycle arrest, and apoptosis. The object of the present study was to investigate the anti-proliferation and apoptosis induction effects of metformin and TSA in osteosarcoma cell line, and to explore the mechanism of metformin and TSA in combination to inhibit the proliferation of osteosarcoma cells. After treating with metformin and TSA, the viability of osteosarcoma cell lines (MG-63 and LM8) was analyzed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) at various concentrations, cell cycle analysis of MG-63 and LM8 cell was performed by flow cytometry. Real-time polymerase chain reaction and Western Blotting were performed to determine the expression of apoptosis-related genes and proteins such as Caspase-3, Bcl-2/Bax, Cyclin D1, and p21. Protein expression of the molecules involved in 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway after treatment with combination was determined by Western blotting. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish the murine model; tumor weight and tumor volume were monitored after drug administration separately or combined via the intraperitoneal (i.p.) route. MTT assays showed that the viability of osteosarcoma cell lines in the combination group (10 mM metformin, 0.3 μM TSA) decreased in a concentration- and time-dependent manner; moreover, the cell cycle of MG-63 and LM8 in the combination group could be arrested in G1/G2 phase higher number compared with drug use separately. Furthermore, a combination of these drugs does not act via the AMPK signaling pathway to induce MG-63 osteosarcoma cell line growth inhibition and apoptosis. As data have showed here, metformin cotreatment increased TSA antitumor effects and have a synergistic effect on osteosarcoma cell line proliferation and apoptosis.DNA and cell biology 03/2013; 32(4). DOI:10.1089/dna.2012.1926 · 2.06 Impact Factor