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.

TY - JOUR

T1 - 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.

AU - Skov, Søren

AU - Pedersen, Marianne Terndrup

AU - Andresen, Lars

AU - Straten, Per Thor

AU - Woetmann, Anders

AU - Odum, Niels

N1 - Keywords: Antibiotics, Antineoplastic; Apoptosis; Cell Line, Tumor; Depsipeptides; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Histocompatibility Antigens Class I; Histone Deacetylases; Humans; Jurkat Cells; Killer Cells, Natural; Neoplasms; T-Lymphocytes

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-05-0599

DO - 10.1158/0008-5472.CAN-05-0599

M3 - Journal article

C2 - 16322264

SN - 0008-5472

VL - 65

SP - 11136

EP - 11145

JO - Cancer Research

JF - Cancer Research

IS - 23

ER -