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

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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‐α 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‐α 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‐α 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‐α by depsipeptide was due to transcriptional activation of the TNF‐α gene through hyperacetylation of histones H3 and H4 in its promoter region (−208 to +35). These results suggest that autocrine production of TNF‐α plays a role in the cytotoxicity of depsipeptide against a subset of leukemias.