Inhibitors of Histone Deacetylase Suppress the Growth of MCF-7 Breast Cancer Cells
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Inhibitors of histone deacetylase are attracting increasing interest due to their influence on transcription, differentiation, and apoptosis. We have investigated two synthetic inhibitors 3 and 4 of histone deacetylase and the natural product inhibitor trichostatin A for their ability to suppress the growth of MCF-7 breast cancer cells and here present complete and improved synthetic procedures. The compounds show a dose dependent inhibition of growth with activities in the low micromolar and nanomolar range. Trichostatin shows cytocidal effects at 100 nM and still has activity comparable to cisplatin (0.5 μM) at 10 nM. Whereas the synthetic inhibitor 3 has cytocidal activity at 10 μM compound 4 shows a maximum of 40% growth suppression at that concentration.Keywords:
Trichostatin A
Histone deacetylase inhibitor
MCF-7
Growth inhibition
HDAC11
Histone deacetylase 5
Trichostatin A
Histone deacetylase inhibitor
HDAC10
HDAC11
Histone deacetylase 5
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Supplementary Methods, Figures 1-4 from Histone Deacetylase Cytoplasmic Trapping by a Novel Fluorescent HDAC Inhibitor
HDAC11
Histone deacetylase 5
HDAC10
Histone deacetylase inhibitor
Histone deacetylase 2
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Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is a putative tumor suppressor whose expression can be increased by drug treatment. Glioblastoma is the most common central nervous system tumor, is associated with high morbidity and mortality, and responds poorly to surgical, chemical, and radiation therapy. The histone deacetylase inhibitors are under current consideration as therapeutic agents in treating glioblastoma. We investigated whether trichostatin A (TSA) would alter the expression of NAG-1 in glioblastoma cells. The DNA demethylating agent 5-aza-dC did not increase NAG-1 expression, but TSA up-regulated NAG-1 expression and acted synergistically with 5-aza-dC to induce NAG-1 expression. TSA indirectly increases NAG-1 promoter activity and increases NAG-1 mRNA and protein expression in the T98G human glioblastoma cell line. TSA also increases the expression of transcription factors Sp-1 and Egr-1. Small interfering RNA experiments link NAG-1 expression to apoptosis induced by TSA. Reporter gene assays, specific inhibition by small interfering RNA transfections, and chromatin immunoprecipitation assays indicate that Egr-1 and Sp-1 mediate TSA-induced NAG-1 expression. TSA also increases the stability of NAG-1 mRNA. TSA-induced NAG-1 expression involves multiple mechanisms at the transcriptional and post-transcriptional levels.
Trichostatin A
Histone deacetylase inhibitor
HDAC11
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Treatment of cultured cells with sodium butyrate, that is the histone deacetylase inhibitor, induces the histone hyperacetylation and the expressions of various mammalian genes without affecting the level of protein synthesis. However, butyrate is a non‐specific inhibitor of deacetylase because of its effects on various other enzymes and nuclear proteins other than histones. On the other hand, Trichostatin A (TSA) was recently found to be a potent and specific inhibitor of histone deacetylase. We examined the effect of TSA on the expression of mouse cytokeratin A ( endo A ). TSA increased endo A expression in F9 cells, and was efffective at a much lower concentration than sodium butyrate. We also examined the changes of chromatin structure induced by the two drugs by a DNase I‐hypersensitivity assay. Both drugs induced the formation of a DNase I‐hypersensitive site (DH site) in only the promoter region. The precise mechanism(s) by which the two drugs increase endo A gene expression is unknown, but these results suggest that endo A expression is induced by inhibition of histone deacetylase and that the effect is at the transcriptional level.
Trichostatin A
Sodium butyrate
HDAC11
Histone deacetylase inhibitor
Histone deacetylase 5
Histone deacetylase 2
HDAC10
HDAC4
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Trichostatin A
HDAC11
Corepressor
Histone deacetylase inhibitor
Histone deacetylase 5
HDAC4
HDAC10
Histone deacetylase 2
HDAC1
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Histone deacetylase (HDAC) inhibitors inhibit the proliferation of transformed cells in vitro, restrain tumor growth in animals, and are currently being actively exploited as potential anticancer agents. To identify gene targets of the HDAC inhibitor trichostatin A (TSA), we compared the gene expression profiles of BALB/c-3T3 cells treated with or without TSA. Our results show that TSA up-regulates the expression of the gene encoding growth-differentiation factor 11 (Gdf11), a transforming growth factor beta family member that inhibits cell proliferation. Detailed analyses indicated that TSA activates the gdf11 promoter through a conserved CCAAT box element. A comprehensive survey of human HDACs revealed that HDAC3 is necessary and sufficient for the repression of gdf11 promoter activity. Chromatin immunoprecipitation assays showed that treatment of cells with TSA or silencing of HDAC3 expression by small interfering RNA causes the hyperacetylation of Lys-9 in histone H3 on the gdf11 promoter. Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression.
Trichostatin A
HDAC3
HDAC11
Histone deacetylase 5
Chromatin immunoprecipitation
Histone deacetylase inhibitor
Histone deacetylase 2
Derepression
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Trichostatin A
Histone deacetylase inhibitor
HDAC11
Histone deacetylase 5
HDAC10
HDAC4
Histone deacetylase 2
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Trichostatin A
Histone deacetylase inhibitor
HDAC10
HDAC11
Histone deacetylase 5
Histone deacetylase 2
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Trichostatin A
Sodium butyrate
HDAC11
Histone deacetylase 5
HDAC10
HDAC4
K562 cells
Histone deacetylase 2
Histone deacetylase inhibitor
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