Abstract
We show that histone deacetylase (HDAC) inhibitors lead to functional expression of MHC class I-related chain A and B (MICA/B) on cancer cells, making them potent targets for natural killer (NK) cell-mediated killing through a NK group 2, member D (NKG2D) restricted mechanism. Blocking either apoptosis or oxidative stress caused by HDAC inhibitor treatment did not affect MICA/B expression, suggesting involvement of a separate signal pathway not directly coupled to induction of cell death. HDAC inhibitor treatment induced glycogen synthase kinase-3 (GSK-3) activity and down-regulation of GSK-3 by small interfering RNA or by different inhibitors showed that GSK-3 activity is essential for the induced MICA/B expression. We thus present evidence that cancer cells which survive the direct induction of cell death by HDAC inhibitors become targets for NKG2D-expressing cells like NK cells, gammadelta T cells, and CD8 T cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects
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Apoptosis / immunology
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Cell Line, Tumor
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Depsipeptides / pharmacology
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Enzyme Inhibitors / pharmacology*
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Glycogen Synthase Kinase 3 / immunology
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Glycogen Synthase Kinase 3 / metabolism*
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Histocompatibility Antigens Class I / biosynthesis*
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Histocompatibility Antigens Class I / immunology
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Histone Deacetylase Inhibitors*
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Histone Deacetylases / immunology
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Humans
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Jurkat Cells
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Killer Cells, Natural / immunology*
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Neoplasms / drug therapy
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Neoplasms / enzymology
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Neoplasms / immunology*
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T-Lymphocytes / drug effects
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
Substances
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Antibiotics, Antineoplastic
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Depsipeptides
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Enzyme Inhibitors
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Histocompatibility Antigens Class I
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Histone Deacetylase Inhibitors
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MHC class I-related chain A
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MICB antigen
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romidepsin
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Glycogen Synthase Kinase 3
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Histone Deacetylases