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Interferon Regulatory Factor-8 Is Important for Histone Deacetylase Inhibitor-Mediated Antitumor Activity

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 fo...

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Autores principales: Banik, Debarati, Khan, A. Nazmul H., Walseng, Even, Segal, Brahm H., Abrams, Scott I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446900/
https://www.ncbi.nlm.nih.gov/pubmed/23028998
http://dx.doi.org/10.1371/journal.pone.0045422
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author Banik, Debarati
Khan, A. Nazmul H.
Walseng, Even
Segal, Brahm H.
Abrams, Scott I.
author_facet Banik, Debarati
Khan, A. Nazmul H.
Walseng, Even
Segal, Brahm H.
Abrams, Scott I.
author_sort Banik, Debarati
collection PubMed
description 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.
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spelling pubmed-34469002012-10-01 Interferon Regulatory Factor-8 Is Important for Histone Deacetylase Inhibitor-Mediated Antitumor Activity Banik, Debarati Khan, A. Nazmul H. Walseng, Even Segal, Brahm H. Abrams, Scott I. PLoS One Research Article 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. Public Library of Science 2012-09-19 /pmc/articles/PMC3446900/ /pubmed/23028998 http://dx.doi.org/10.1371/journal.pone.0045422 Text en © 2012 Banik et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Banik, Debarati
Khan, A. Nazmul H.
Walseng, Even
Segal, Brahm H.
Abrams, Scott I.
Interferon Regulatory Factor-8 Is Important for Histone Deacetylase Inhibitor-Mediated Antitumor Activity
title Interferon Regulatory Factor-8 Is Important for Histone Deacetylase Inhibitor-Mediated Antitumor Activity
title_full Interferon Regulatory Factor-8 Is Important for Histone Deacetylase Inhibitor-Mediated Antitumor Activity
title_fullStr Interferon Regulatory Factor-8 Is Important for Histone Deacetylase Inhibitor-Mediated Antitumor Activity
title_full_unstemmed Interferon Regulatory Factor-8 Is Important for Histone Deacetylase Inhibitor-Mediated Antitumor Activity
title_short Interferon Regulatory Factor-8 Is Important for Histone Deacetylase Inhibitor-Mediated Antitumor Activity
title_sort interferon regulatory factor-8 is important for histone deacetylase inhibitor-mediated antitumor activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446900/
https://www.ncbi.nlm.nih.gov/pubmed/23028998
http://dx.doi.org/10.1371/journal.pone.0045422
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