The histone deacetylase inhibitor trichostatin a promotes apoptosis and antitumor immunity in glioblastoma cells

Anticancer Res. 2013 Apr;33(4):1351-60.


Histone deacetylase inhibitors (HDACi) have been described as multifunctional anticancer agents. The failure of conventional therapy for glioblastoma (GBM) renders this tumor an attractive target for immunotherapy. Innate immune cells, such as natural killer (NK) cells, play a crucial role in antitumor immune responses. Here, we describe how the HDACi trichostatin A (TSA) promotes apoptosis of tumor cells, as well as augments anti-GBM innate immune responses. In vitro treatment of GBM cells with TSA results in an up-regulation of the natural killer group-2 member-D (NKG2D) ligands major histocompatibility complex class I-related chain (MIC)-A and UL16 binding protein (ULBP)-2 at both mRNA and protein levels, rendering them susceptible to NK cell-mediated lysis. In vivo, TSA delays tumor growth of GBM xenografts. Both the in vitro and in vivo antitumor effect of TSA was significantly reduced by blocking NK cell activity. Our data suggest that HDACi, especially in combination with other clinical immunotherapeutical approaches, may be considered in a combined therapeutic approach for GBM.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Blotting, Western
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / immunology
  • Brain Neoplasms / pathology*
  • Cell Proliferation / drug effects*
  • Cytotoxicity, Immunologic
  • Female
  • Flow Cytometry
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • Glioblastoma / drug therapy
  • Glioblastoma / immunology
  • Glioblastoma / pathology*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology
  • Mice
  • Mice, Nude
  • NK Cell Lectin-Like Receptor Subfamily K / genetics
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Tumor Cells, Cultured


  • GPI-Linked Proteins
  • Histocompatibility Antigens Class I
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Intercellular Signaling Peptides and Proteins
  • KLRK1 protein, human
  • MHC class I-related chain A
  • MICB antigen
  • NK Cell Lectin-Like Receptor Subfamily K
  • RNA, Messenger
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • ULBP2 protein, human
  • trichostatin A