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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

Häcker, S
; 
Dittrich, A
; 
Mohr, A
; 
Schweitzer, T
; 
Rutkowski, S
; 
Krauss, J
; 
Debatin, K-M
; 
Fulda, S
Repository DOI
Publication Date
2009-07-13
Keywords
caspase-8, apoptosis, trail, hdaci, medulloblastoma, up-regulating caspase-8, drug-induced apoptosis, interferon-gamma, death receptor, cell-death, childhood medulloblastoma, pancreatic-carcinoma, neuroblastoma-cells, ewings-sarcoma, tumor cells
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Häcker, S; Dittrich, A; Mohr, A; Schweitzer, T; Rutkowski, S; Krauss, J; Debatin, K-M; Fulda, S (2009). 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 (35), 3097-3110
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)-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. Oncogene (2009) 28, 3097-3110; doi: 10.1038/onc.2009.161; published online 13 July 2009
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Publisher
Springer Nature
Publisher DOI
10.1038/onc.2009.161
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Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (2)