Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B.
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.
Skov
Søren
S
Institute of Molecular Biology and Physiology, University of Copenhagen, Denmark. s.skov@immi.ku.dk
Pedersen
Marianne Terndrup
MT
Andresen
Lars
L
Straten
Per Thor
PT
Woetmann
Anders
A
Odum
Niels
N
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000276:immunology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; C099187:MHC class I-related chain A; C098080:MICB antigen; C087123:romidepsin; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases