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

Koji Yamanegi; Junko Yamane; Kenta Kobayashi; Nahoko Kato-Kogoe; Hideki Ohyama; Keiji Nakasho; Naoko Yamada; Masaki Hata; Toshihiro Nishioka; Satoru Fukunaga; Hiroyuki Futani; Haruki Okamura; Nobuyuki Terada

doi:10.3892/or_00001026

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

Oncol Rep. 2010 Dec;24(6):1621-7. doi: 10.3892/or_00001026.

Authors

Koji Yamanegi¹, Junko Yamane, Kenta Kobayashi, Nahoko Kato-Kogoe, Hideki Ohyama, Keiji Nakasho, Naoko Yamada, Masaki Hata, Toshihiro Nishioka, Satoru Fukunaga, Hiroyuki Futani, Haruki Okamura, Nobuyuki Terada

Affiliation

¹ Department of Pathology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. [email protected]

PMID: 21042760
DOI: 10.3892/or_00001026

Abstract

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.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Surface / genetics
Antigens, Surface / metabolism
Bone Neoplasms / genetics
Bone Neoplasms / immunology
Bone Neoplasms / metabolism
Bone Neoplasms / therapy*
Cell Line, Tumor
Cell Membrane / drug effects
Cell Membrane / metabolism
Combined Modality Therapy
Gene Expression Regulation, Neoplastic / drug effects
Histocompatibility Antigens Class I / genetics*
Histocompatibility Antigens Class I / metabolism
Histone Deacetylase Inhibitors / pharmacology
Humans
Immunity, Cellular / drug effects*
Immunotherapy / methods
Killer Cells, Natural / immunology*
Ligands
NK Cell Lectin-Like Receptor Subfamily K / metabolism
Osteosarcoma / genetics
Osteosarcoma / immunology
Osteosarcoma / metabolism
Osteosarcoma / therapy*
Protein Isoforms / genetics
Protein Isoforms / metabolism
Solubility
Up-Regulation / drug effects
Up-Regulation / genetics
Valproic Acid / pharmacology*

Substances

Antigens, Surface
Histocompatibility Antigens Class I
Histone Deacetylase Inhibitors
KLRK1 protein, human
Ligands
MHC class I-related chain A
MICB antigen
NK Cell Lectin-Like Receptor Subfamily K
Protein Isoforms
Valproic Acid