Histone deacetylase regulation of immune gene expression in tumor cells
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Histone deacetylase regulation of immune gene expression in tumor cells A. Nazmul H. Khan Æ Thomas B. Tomasi
Published online: 15 June 2007 Ó Humana Press Inc. 2007
Abstract Epigenetic modifications of chromatin, such as histone acetylation, are involved in repression of tumor antigens and multiple immune genes that are thought to facilitate tumor escape. The status of acetylation in a cell is determined by the balance of the activities of histone acetyltransferases and histone deacetylases. Inhibitors of histone deacetylase (HDACi) can enhance the expression of immunologically important molecules in tumor cells and HDACi treated tumor cells are able to induce immune responses in vitro and in vivo. Systemic HDACi are in clinical trails in cancer and also being used in several autoimmune disease models. To date, 18 HDACs have been reported in human cells and more than thirty HDACi identified, although only a few immune targets of these inhibitors have been identified. Here, we discuss the molecular pathways employed by HDACi and their potential role in inducing immune responses against tumors. We review data suggesting that selection of target specific HDACi and combinations with other agents and modalities, including those that activate stress pathways, may further enhance the efficacy of epigenetic therapies. Keywords Epigenetic gene regulation Tumor vaccine Histone deacetylase inhibitor Immune response Inflammatory cytokine
Introduction Histone deacetylase inhibitors [HDACi] are a new generation of chemical agents being used to develop therapy against cancer and other diseases [1–3]. Many of these
A. N. H. Khan (&) T. B. Tomasi Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA e-mail: [email protected] T. B. Tomasi Departments of Medicine and Microbiology & Immunology, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA
Immunol Res (2008) 40:164–178
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compounds, including trichostatin A [TSA] the first HDACi identified, were studied originally as differentiating agents. Several HDACi are in clinical trials based on their ability to inhibit cell growth and induce apoptosis and have shown significant activity against a spectrum of hematological and solid tumors [4, 5]. Monitoring gene effects following treatments with HDACi has furthered our understanding the role of epigenetic regulation in cancer. Many studies have identified numerous genes regulated epigenetically in cancer (reviewed in 6, 7) and several reviews have focused on the epigenetics of immune genes particularly in regulating T and B-cell differentiation [8–10]. Recent studies have also suggested that epigenetic silencing of immune genes in cancer may be as, or more, frequent a cause of gene repression as are mutations [11]. Here we consider additional mechanisms for the HDACi mediated effects in cancer cells and review evidence suggesting that cellular stress can enhance the expression of re
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