Sodium valproate, a histone deacetylase inhibitor, augments the expression of cell-surface NKG2D ligands, MICA/B, without increasing their soluble forms to enhance susceptibility of human osteosarcoma cells to NK cell-mediated cytotoxicity.
MHC class I-related chain molecules A and B (MICA and B) expressed on the cell-surface of tumor cells are ligands for an activating receptor, NKG2D, expressed on natural killer (NK) cells and stimulate the NK cell-mediated cytotoxicity. On the other hand, the soluble form of MICA and B produced by proteolytic cleavage of cell-surface MIC interferes with NK cell-mediated cytotoxicity. We investigated effect of sodium valproate (VPA), a histone deacetylase inhibitor, on the production of cell-surface and soluble MICA and B and NK cell-mediated cytotoxicity in four human osteosarcoma cells. VPA at 0.5 and 1.0 mM induced acetylation of histones bound to MICA and B gene promoters, increased cell-surface but not soluble MICA and B, and augmented the susceptibility of osteosarcoma cells to NK cell-mediated cytotoxicity. The present results indicate that VPA sensitizes human osteosarcoma cells to cytotoxicity of NK cells.
Department of Pathology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. yamanegi@hyo-med.ac.jp
Koji
K
Yamanegi
Junko
J
Yamane
Kenta
K
Kobayashi
Nahoko
N
Kato-Kogoe
Hideki
H
Ohyama
Keiji
K
Nakasho
Naoko
N
Yamada
Masaki
M
Hata
Toshihiro
T
Nishioka
Satoru
S
Fukunaga
Hiroyuki
H
Futani
Haruki
H
Okamura
Nobuyuki
N
Terada
D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003131:Combined Modality Therapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology*
D000954:Antigens, Surface; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020033:Protein Isoforms; D014635:Valproic Acid