Abstract
Inhibition of histone deacetylase (HDAC) is a novel strategy for the treatment of leukemias via restoration of aberrantly silenced genes. In this study, we conducted a detailed analysis of anti-leukemic effects of an HDAC inhibitor (HDI), depsipeptide (FK228), using myeloid leukemia cell lines HL-60 and K562. DNA chip analysis revealed upregulation of TNF-alpha mRNA and a number of molecules involved in TNF-signaling such as TRAF-6, caspases-10, and -7 in depsipeptide-treated HL-60 cells, which prompted us to examine the involvement of the TNF/TNF receptor system in the anti-leukemic effects of the drug. Upregulation of TNF-alpha was induced by depsipeptide in HL-60 and K562 cells, which expressed type I TNF receptors (TNF-RI). Depsipeptide activated caspases-8 and -10, which in turn cleave caspases-3 and -7, leading to apoptotic cell death in both cell lines. Anti-TNF-alpha neutralizing antibody and short interfering RNA (siRNA) against TNF-RI alleviated the activation of the caspase cascade and the induction of apoptosis, indicating the presence of an autocrine loop. Finally, we demonstrated that the enhanced production of TNF-alpha by depsipeptide was due to transcriptional activation of the TNF-alpha gene through hyperacetylation of histones H3 and H4 in its promoter region (-208 to +35). These results suggest that autocrine production of TNF-alpha plays a role in the cytotoxicity of depsipeptide against a subset of leukemias.
Copyright 2004 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Antibiotics, Antineoplastic / pharmacology
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Antibiotics, Antineoplastic / therapeutic use
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Antibodies / pharmacology
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Apoptosis / drug effects*
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Apoptosis / physiology
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Autocrine Communication / drug effects
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Autocrine Communication / physiology
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Caspases / drug effects
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Caspases / metabolism
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / metabolism
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Depsipeptides / pharmacology*
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Depsipeptides / therapeutic use
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Gene Expression Profiling
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HL-60 Cells
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Histone Deacetylase Inhibitors*
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Histone Deacetylases / metabolism
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Histones / metabolism
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Humans
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K562 Cells
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Leukemia / drug therapy*
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Leukemia / metabolism
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Leukemia / physiopathology
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Oligonucleotide Array Sequence Analysis
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / genetics
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Tumor Necrosis Factor / drug effects
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I / drug effects
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology
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Tumor Necrosis Factor-alpha / genetics*
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Tumor Necrosis Factor-alpha / metabolism
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Up-Regulation / drug effects
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Up-Regulation / physiology
Substances
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Antibiotics, Antineoplastic
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Antibodies
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Depsipeptides
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Histones
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Tumor Necrosis Factor-alpha
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romidepsin
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Caspases
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Histone Deacetylases