Involvement of the tumor necrosis factor (TNF)/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide (FK228)

J Cell Physiol. 2005 May;203(2):387-97. doi: 10.1002/jcp.20235.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Antibiotics, Antineoplastic / pharmacology
  • Antibiotics, Antineoplastic / therapeutic use
  • Antibodies / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Autocrine Communication / drug effects
  • Autocrine Communication / physiology
  • Caspases / drug effects
  • Caspases / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Depsipeptides / pharmacology*
  • Depsipeptides / therapeutic use
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Gene Expression Profiling
  • HL-60 Cells
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • K562 Cells
  • Leukemia / drug therapy*
  • Leukemia / metabolism
  • Leukemia / physiopathology
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Tumor Necrosis Factor / drug effects
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / drug effects
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Antibiotics, Antineoplastic
  • Antibodies
  • Depsipeptides
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • romidepsin
  • Caspases
  • Histone Deacetylases