Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells

Oncogene. 2004 Aug 19;23(37):6261-71. doi: 10.1038/sj.onc.1207830.


Death receptor 5 (DR5) is a receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. Here, we report that histone deacetylase inhibitors (HDACIs) such as trichostatin A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid (SAHA) upregulated DR5 expression in various human malignant tumor cells. An RNase protection assay demonstrated that HDACIs induced DR5 mRNA markedly but not that of other death receptor family members in Jurkat cells. HDACIs increased DR5 mRNA and protein in a dose- and time-dependent manner. We also show TSA increased DR5 promoter activity using a luciferase promoter assay. Furthermore, we demonstrated that HDACIs strongly sensitized exogenous soluble recombinant human TRAIL-induced apoptosis synergistically in Jurkat and HL-60 cells that were tolerant to TRAIL alone. The combined use of HDACIs and TRAIL in suboptimal concentrations induced Bid cleavage and activation of caspase-8, -10, -3, and -9. Human recombinant DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 and -10 inhibitors efficiently reduced apoptosis induced by cotreatment with HDACIs and TRAIL. Furthermore, TSA did not significantly induce DR5 protein and HDACIs did not enhance TRAIL-induced apoptosis in normal human peripheral blood mononuclear cells. These results suggest that this combined treatment with HDACIs and TRAIL is a promising strategy for new cancer therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Blotting, Western
  • Carrier Proteins / metabolism
  • Caspases / metabolism
  • Cell Line, Tumor
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydrolysis
  • Membrane Glycoproteins / physiology*
  • Promoter Regions, Genetic
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / physiology*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / physiology*
  • Up-Regulation / drug effects*


  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Membrane Glycoproteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Caspases