Histone Deacetylase Inhibitors Down-Regulate bcl-2 Expression and Induce Apoptosis in t(14;18) Lymphomas
| Autor: | Linda M. Boxer, Hong Duan, Caroline A. Heckman |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Lymphoma
B-Cell Gene Expression Down-Regulation Histone Deacetylase 2 Apoptosis Biology Hydroxamic Acids Histone Deacetylases Translocation Genetic Histones chemistry.chemical_compound Cell Line Tumor medicine Humans RNA Messenger Enzyme Inhibitors Promoter Regions Genetic Molecular Biology Chromosomes Human Pair 14 Histone deacetylase 5 Binding Sites Histone deacetylase 2 Cell Cycle Acetylation Sodium butyrate Cell Biology Molecular biology Histone H3 deacetylation Histone Deacetylase Inhibitors Repressor Proteins Trichostatin A Proto-Oncogene Proteins c-bcl-2 chemistry Barbiturates Mutation CCAAT-Enhancer-Binding Proteins Cancer research Histone deacetylase Chromosomes Human Pair 18 Protein Kinases Chromatin immunoprecipitation medicine.drug |
| Zdroj: | Molecular and Cellular Biology. 25:1608-1619 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.25.5.1608-1619.2005 |
| Popis: | Histone deacetylase (HDAC) inhibitors are promising antitumor agents, but they have not been extensively explored in B-cell lymphomas. Many of these lymphomas have the t(14;18) translocation, which results in increased bcl-2 expression and resistance to apoptosis. In this study, we examined the effects of two structurally different HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on the cell cycle, apoptosis, and bcl-2 expression in t(14;18) lymphoma cells. We found that in addition to potent cell cycle arrest, TSA and NaB also dramatically induced apoptosis and down-regulated bcl-2 expression, and overexpression of bcl-2 inhibited TSA-induced apoptosis. The repression of bcl-2 by TSA occurred at the transcriptional level. Western blot analysis and quantitative chromatin immunoprecipitation (ChIP) assay showed that even though HDAC inhibitors increased overall acetylation of histones, localized histone H3 deacetylation occurred at both bcl-2 promoters. TSA treatment increased the acetylation of the transcription factors Sp1 and C/EBPalpha and decreased their binding as well as the binding of CBP and HDAC2 to the bcl-2 promoters. Mutation of Sp1 and C/EBPalpha binding sites reduced the TSA-induced repression of bcl-2 promoter activity. This study provides a mechanistic rationale for the use of HDAC inhibitors in the treatment of human t(14;18) lymphomas. |
| Databáze: | OpenAIRE |
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