Involvement of the tumor necrosis factor (TNF)/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide (FK228).
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.
Sutheesophon
Krittaya
K
Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, 33311-1 Yakushiji, Minamikachi-machi, Tochigi 329-0498, Japan.
Nishimura
Noriko
N
Kobayashi
Yukiko
Y
Furukawa
Yutaka
Y
Kawano
Mikihiko
M
Itoh
Kouichi
K
Kano
Yasuhiko
Y
Ishii
Hideshi
H
Furukawa
Yusuke
Y
D000107:Acetylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020869:Gene Expression Profiling; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C087123:romidepsin; D020169:Caspases; D006655:Histone Deacetylases