Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8

Oncogene. 2009 Sep 3;28(35):3097-110. doi: 10.1038/onc.2009.161. Epub 2009 Jul 13.


Evasion of apoptosis can be caused by epigenetic silencing of caspase-8, a key component of the extrinsic apoptosis pathway. Loss of caspase-8 correlates with poor prognosis in medulloblastoma, which highlights the relevance of strategies to upregulate caspase-8 to break apoptosis resistance. Here, we develop a new combinatorial approach, that is treatment using histone deacetylase inhibitors (HDACI) together with interferon (IFN)-gamma, to restore caspase-8 expression and to overcome resistance to the death-receptor ligand TNF-related apoptosis-inducing ligand (TRAIL) in medulloblastoma in vitro and in vivo. HDACI, for example, valproic acid (VA), suberoylanilide hydroxamic acid (SAHA) and MS-275, cooperate with IFN-gamma to upregulate caspase-8 in cancer cells lacking caspase-8, thereby restoring sensitivity to TRAIL-induced apoptosis. Molecular studies show that VA promotes histone acetylation and acts in concert with IFN-gamma to stimulate caspase-8 promoter activity. The resulting increase in caspase-8 mRNA and protein expression leads to enhanced TRAIL-induced activation of caspase-8 at the death-inducing signaling complex, mitochondrial outer-membrane permeabilization and caspase-dependent cell death. Intriguingly, pharmacological or genetic inhibition of caspase-8 also abolishes the VA/IFN-gamma-mediated sensitization for TRAIL-induced apoptosis. It is important to note that VA and IFN-gamma restore caspase-8 expression and sensitivity to TRAIL in primary medulloblastoma samples and significantly potentiate TRAIL-mediated suppression of medulloblastoma growth in vivo. These findings provide the rationale for further (pre)clinical evaluation of VA and IFN-gamma to restore caspase-8 expression and apoptosis sensitivity in cancers with caspase-8 silencing and open new perspectives to overcome TRAIL resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / pharmacology
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cerebellar Neoplasms
  • Drug Combinations
  • Drug Resistance, Neoplasm / drug effects*
  • Enzyme Inhibitors / classification
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic
  • Gene Silencing
  • Heterozygote
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Interferon-gamma / pharmacology*
  • Medulloblastoma
  • Neoplasms
  • Pyridines / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Time Factors
  • Valproic Acid / pharmacology
  • Vorinostat


  • Benzamides
  • Drug Combinations
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Pyridines
  • TNF-Related Apoptosis-Inducing Ligand
  • entinostat
  • Vorinostat
  • Valproic Acid
  • Interferon-gamma
  • Caspase 8