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: Various pre-clinical and clinical studies have linked diabetes and breast cancer, but, little is known regarding the molecular mechanism involved. The present study was aimed to investigate the effect of high glucose and insulin in breast cancer cells (MCF-7; non-invasive, hormone dependent and MDA-MB-231; invasive, hormone independent). In contrast to MCF-7 cells, high glucose augmented proliferation of MDA-MB-231 cells as observed by MTT and BrdU assay. High glucose condition led to increased expression of Cyclin D1, de-phosphorylation of p38 and increased phosphorylation of ERK in MDA-MB-231 cells and not in MCF-7 cells. Interestingly, we observed increased phosphorylation of GSK-3β, NF-κB and ERα only in MCF-7 cells, highlighting their role as potential targets in preventing progression of breast cancer under high glucose and insulin condition. Furthermore, insulin treatment under high glucose condition resulted in increased histone H3 phosphorylation and de-acetylation only in MDA-MB-231 cells. Taken together, we provide first evidence that high glucose and insulin promotes proliferation of MDA-MB-231 cells, by differential alteration of GSK-3β, NF-κB, ERα expression and histone H3 modifications, which may directly or indirectly modulate the expression of genes involved in its proliferation.Journal of Molecular Endocrinology 05/2013; · 3.58 Impact Factor
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ABSTRACT: To explore the effect of lysine acetylation in related proteins on regulation of the proliferation of gastric cancer cells, and determine the lysine-acetylated proteins and the acetylated modified sites in AGS gastric cancer cells. The CCK-8 experiment and flow cytometry were used to observe the changes in proliferation and cycle of AGS cells treated with trichostatin A (TSA). Real time polymerase chain reaction and Western blotting were used to observe expression changes in p21, p53, Bax, Bcl-2, CDK2, and CyclinD1 in gastric cancer cells exposed to TSA. Cytoplasmic proteins in gastric cancer cells before and after TSA treatment were immunoprecipitated with anti-acetylated lysine antibodies, separated using sodium dodecyl sulfate polyacrylamide gel electrophoresis gel and silver-stained to detect the proteins by mass spectrometry after removal of the gel. The acetylated proteins in AGS cells were enriched with lysine-acetylated antibodies, and a high-resolution mass spectrometer was used to detect the acetylated proteins and modified sites. TSA significantly inhibited AGS cell proliferation, and promoted cell apoptosis, leading to AGS cell cycle arrest in G0/G1 and G2/M phases, especially G0/G1 phase. p21, p53 and Bax gene expression levels in AGS cells were increased with TSA treatment duration; Bcl-2, CDK2, and CyclinD1 gene expression levels were decreased with TSA treatment duration. Two unknown protein bands, 72 kDa (before exposure to TSA) and 28 kDa (after exposure to TSA), were identified by silver-staining after immunoprecipitation of AGS cells with the lysine-acetylated monoclonal antibodies. Mass spectrometry showed that the 72 kDa protein band may be PKM2 and the 28 kDa protein band may be ATP5O. The acetylated proteins and modified sites in AGS cells were determined. TSA can inhibit gastric cancer cell proliferation, which possibly activated signaling pathways in a variety of tumor-associated factors. ATP5O was obviously acetylated in AGS cells following TSA treatment.World Journal of Gastroenterology 06/2013; 19(21):3226-40. · 2.55 Impact Factor
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ABSTRACT: Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically. The correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB). IHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis. Down-regulation of intratumoral and peritumoral Sirt3 were both associated with poor outcome in HCC, moreover, intratumoral Sirt3 was a favorable prognostic predictor in early stage patients.BMC Cancer 04/2014; 14(1):297. · 3.33 Impact Factor