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

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Abstract

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)-γ, 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-γ 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-γ 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-γ-mediated sensitization for TRAIL-induced apoptosis. It is important to note that VA and IFN-γ 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-γ to restore caspase-8 expression and apoptosis sensitivity in cancers with caspase-8 silencing and open new perspectives to overcome TRAIL resistance.

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Acknowledgements

We thank R Agami (The Netherlands Cancer Institute, Amsterdam, Netherlands) for providing pRETRO-SUPER vector, CA Schmitt (Berlin, Germany) for mouse Bcl-2 vector, M. Romani (Genova, Italy) for caspase-8 pBL-CAT3 promoter construct, Apoxis (Lausanne, Switzerland) for mega-Fas ligand and F Beguinot (Naples, Italy) for anti-PED antibody. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, IAP6/18 and the European Community (ApopTrain, APO-SYS) (to SF).

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  1. S Rutkowski

    Present address: 5Current address: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,

Authors and Affiliations

  1. University Children's Hospital, Ulm, Germany

    S Häcker, A Dittrich, K-M Debatin & S Fulda

  2. National University of Ireland, National Centre for Biomedical Engineering Science (NCBES), Molecular Therapeutics Group, Galway, Ireland

    A Mohr

  3. Department of Neurosurgery, University of Würzburg, Würzburg, Germany

    T Schweitzer & J Krauss

  4. Department of Pediatrics, University of Würzburg, Würzburg, Germany

    S Rutkowski

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  1. S Häcker
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Correspondence to S Fulda.

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Häcker, S., Dittrich, A., Mohr, A. et al. Histone deacetylase inhibitors cooperate with IFN-γ to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8. Oncogene 28, 3097–3110 (2009). https://doi.org/10.1038/onc.2009.161

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