title: Interferon regulatory factor-8 is important for histone deacetylase inhibitor-mediated antitumor activity.
abstract: The notion that epigenetic alterations in neoplasia are reversible has provided the rationale to identify epigenetic modifiers for their ability to induce or enhance tumor cell death. Histone deacetylase inhibitors (HDACi) represent one such class of anti-neoplastic agents. Despite great interest for clinical use, little is known regarding the molecular targets important for response to HDACi-based cancer therapy. We had previously shown that interferon regulatory factor (IRF)-8, originally discovered as a leukemia suppressor gene by regulating apoptosis, also regulates Fas-mediated killing in non-hematologic tumor models. Furthermore, we and others have shown that epigenetic mechanisms are involved in repression of IRF-8 in tumors. Therefore, in our preclinical tumor model, we tested the hypothesis that IRF-8 expression is important for response to HDACi-based antitumor activity. In the majority of experiments, we selected the pan-HDACi, Trichostatin A (TSA), because it was previously shown to restore Fas sensitivity to tumor cells. Overall, we found that: 1) TSA alone and more so in combination with IFN-γ enhanced both IRF-8 expression and Fas-mediated death of tumor cells in vitro; 2) TSA treatment enhanced IRF-8 promoter activity via a STAT1-dependent pathway; and 3) IRF-8 was required for this death response, as tumor cells rendered IRF-8 incompetent were significantly less susceptible to Fas-mediated killing in vitro and to HDACi-mediated antitumor activity in vivo. Thus, IRF-8 status may underlie a novel molecular basis for response to HDACi-based antitumor treatment.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Debarati
authors.initials: D
authors.lastname: Banik
authors.forename: A Nazmul H
authors.initials: AN
authors.lastname: Khan
authors.forename: Even
authors.initials: E
authors.lastname: Walseng
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D050794:STAT1 Transcription Factor; D019014:fas Receptor; D000099185:Interferon Regulatory Factor-8; C012589:trichostatin A