Synergistic induction of NY-ESO-1 antigen expression by a novel histone deacetylase inhibitor, valproic acid, with 5-aza-2′-deoxycytidine in glioma cells

NY-ESO-1, one of the most immunogenic cancer/testis antigens, provides attractive targets for cancer immunotherapy. NY-ESO-1 has been demonstrated to be expressed in a range of solid tumors via DNA demethylation and/or histone modification; however, it has been rarely expressed in glioma. The reversibility of these epigenetic aberrations is potentially attractive for glioma treatment with DNA-methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), leading to reactivation of silenced genes. We previously demonstrated de novo induction of NY-ESO-1 in glioma cells by DNMTi. In this study, we show that an anticonvulsant, i.e., valproic acid (VPA), also acting as an HDACi, enhances induction of NY-ESO-1 in synergy with DNMTi. Chromatin assays demonstrated that combination of DNMTi and VPA elicited significant DNA demethylation, histone H3 Lys9 demethylation, and acetylation. These findings not only shed light on an epigenetic immunotherapy, but also suggest that the silencing of NY-ESO-1 is mediated by histone modification.