Histone deacetylase regulation of immune gene expression in tumor cells.
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.
Khan
A Nazmul H
AN
Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA. anmnazmul.khan@roswellpark.org
Tomasi
Thomas B
TB
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D020868:Gene Silencing / Q000276:immunology; D051548:Histone Acetyltransferases / Q000276:immunology* / Q000378:metabolism; D006655:Histone Deacetylases / Q000276:immunology* / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000276:immunology
D000970:Antineoplastic Agents; D002843:Chromatin; D004791:Enzyme Inhibitors; D006657:Histones; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases