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

Abstract

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.

Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells

“…Culture with 1.0 mM VPA increased the expression of MICA/B on the surface of osteosarcoma cells and inhibited their secretion of soluble MICA and MICB, confirming the results of our previous report (16). Our previous study showed that 1.0 mM VPA increased the acetylation of histones, suggesting that at least a part of the action of VPA can be ascribed to its action as a HDAC inhibitor (16).…”

“…After 24 h (day 0), VPA was added to the medium at 1.0 mM, and the cells were cultured for another 7 days, with a medium change on day 3. The cells were detached from the dishes, and the expression of membrane-bound MICA/B was analyzed by a flow cytometric analysis, as described previously (16). The percentages of membrane-bound MICA/B-positive cells were determined by flow cytometric analysis, and the effects of VPA were evaluated by determining the ratio of the percentage of positive cells in the treated cultures to the average percentage of positive cells in the untreated control cultures.…”

“…Valproic acid (VPA), a HDAC inhibitor, increases the expression of MICA and MICB on the surface of human osteosarcoma cells (16). Furthermore, VPA decreases the production of soluble MICA and MICB in these cells (16). However, the mechanisms by which VPA decreases the production of soluble MICA and MICB in osteosarcoma cells remains to be elucidated.…”

“…A number of studies have demonstrated that HDAC inhibitors stimulate the expression of cell surface MICA and MICB in a variety of tumors (12)(13)(14)(15). Valproic acid (VPA), a HDAC inhibitor, increases the expression of MICA and MICB on the surface of human osteosarcoma cells (16). Furthermore, VPA decreases the production of soluble MICA and MICB in these cells (16).…”

Valproic acid cooperates with hydralazine to augment the susceptibility of human osteosarcoma cells to Fas- and NK cell-mediated cell death

“…Several studies have demonstrated that HDAC inhibitors stimulate the expression of cell-surface MICA and MICB in a variety of tumors, enhancing the susceptibility of tumor cells to NK cell-mediated cytotoxicity (17)(18)(19)(20)(21). These agents also enhance the expression of cell-surface Fas (22,23), and increase the (24)(25)(26)(27).…”