Cargando…
Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor
BACKGROUND: Histone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregul...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887841/ https://www.ncbi.nlm.nih.gov/pubmed/20585447 http://dx.doi.org/10.1371/journal.pone.0011208 |
_version_ | 1782182595891560448 |
---|---|
author | Kachhap, Sushant K. Rosmus, Nadine Collis, Spencer J. Kortenhorst, Madeleine S. Q. Wissing, Michel D. Hedayati, Mohammad Shabbeer, Shabana Mendonca, Janet Deangelis, Justin Marchionni, Luigi Lin, Jianqing Höti, Naseruddin Nortier, Johan W. R. DeWeese, Theodore L. Hammers, Hans Carducci, Michael A. |
author_facet | Kachhap, Sushant K. Rosmus, Nadine Collis, Spencer J. Kortenhorst, Madeleine S. Q. Wissing, Michel D. Hedayati, Mohammad Shabbeer, Shabana Mendonca, Janet Deangelis, Justin Marchionni, Luigi Lin, Jianqing Höti, Naseruddin Nortier, Johan W. R. DeWeese, Theodore L. Hammers, Hans Carducci, Michael A. |
author_sort | Kachhap, Sushant K. |
collection | PubMed |
description | BACKGROUND: Histone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregulation remains unclear. Here we provide evidence that several DNA repair genes are downregulated by HDAC inhibition and provide a mechanism involving the E2F1 transcription factor in the process. METHODOLOGY/PRINCIPAL FINDINGS: Applying Analysis of Functional Annotation (AFA) on microarray data of prostate cancer cells treated with HDACis, we found a number of genes of the DNA damage response and repair pathways are downregulated by HDACis. AFA revealed enrichment of homologous recombination (HR) DNA repair genes of the BRCA1 pathway, as well as genes regulated by the E2F1 transcription factor. Prostate cancer cells demonstrated a decreased DNA repair capacity and an increased sensitization to chemical- and radio-DNA damaging agents upon HDAC inhibition. Recruitment of key HR repair proteins to the site of DNA damage, as well as HR repair capacity was compromised upon HDACi treatment. Based on our AFA data, we hypothesized that the E2F transcription factors may play a role in the downregulation of key repair genes upon HDAC inhibition in prostate cancer cells. ChIP analysis and luciferase assays reveal that the downregulation of key repair genes is mediated through decreased recruitment of the E2F1 transcription factor and not through active repression by repressive E2Fs. CONCLUSIONS/SIGNIFICANCE: Our study indicates that several genes in the DNA repair pathway are affected upon HDAC inhibition. Downregulation of the repair genes is on account of a decrease in amount and promoter recruitment of the E2F1 transcription factor. Since HDAC inhibition affects several pathways that could potentially have an impact on DNA repair, compromised DNA repair upon HDAC inhibition could also be attributed to several other pathways besides the ones investigated in this study. However, our study does provide insights into the mechanism that governs downregulation of HR DNA repair genes upon HDAC inhibition, which can lead to rationale usage of HDACis in the clinics. |
format | Text |
id | pubmed-2887841 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28878412010-06-22 Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor Kachhap, Sushant K. Rosmus, Nadine Collis, Spencer J. Kortenhorst, Madeleine S. Q. Wissing, Michel D. Hedayati, Mohammad Shabbeer, Shabana Mendonca, Janet Deangelis, Justin Marchionni, Luigi Lin, Jianqing Höti, Naseruddin Nortier, Johan W. R. DeWeese, Theodore L. Hammers, Hans Carducci, Michael A. PLoS One Research Article BACKGROUND: Histone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregulation remains unclear. Here we provide evidence that several DNA repair genes are downregulated by HDAC inhibition and provide a mechanism involving the E2F1 transcription factor in the process. METHODOLOGY/PRINCIPAL FINDINGS: Applying Analysis of Functional Annotation (AFA) on microarray data of prostate cancer cells treated with HDACis, we found a number of genes of the DNA damage response and repair pathways are downregulated by HDACis. AFA revealed enrichment of homologous recombination (HR) DNA repair genes of the BRCA1 pathway, as well as genes regulated by the E2F1 transcription factor. Prostate cancer cells demonstrated a decreased DNA repair capacity and an increased sensitization to chemical- and radio-DNA damaging agents upon HDAC inhibition. Recruitment of key HR repair proteins to the site of DNA damage, as well as HR repair capacity was compromised upon HDACi treatment. Based on our AFA data, we hypothesized that the E2F transcription factors may play a role in the downregulation of key repair genes upon HDAC inhibition in prostate cancer cells. ChIP analysis and luciferase assays reveal that the downregulation of key repair genes is mediated through decreased recruitment of the E2F1 transcription factor and not through active repression by repressive E2Fs. CONCLUSIONS/SIGNIFICANCE: Our study indicates that several genes in the DNA repair pathway are affected upon HDAC inhibition. Downregulation of the repair genes is on account of a decrease in amount and promoter recruitment of the E2F1 transcription factor. Since HDAC inhibition affects several pathways that could potentially have an impact on DNA repair, compromised DNA repair upon HDAC inhibition could also be attributed to several other pathways besides the ones investigated in this study. However, our study does provide insights into the mechanism that governs downregulation of HR DNA repair genes upon HDAC inhibition, which can lead to rationale usage of HDACis in the clinics. Public Library of Science 2010-06-18 /pmc/articles/PMC2887841/ /pubmed/20585447 http://dx.doi.org/10.1371/journal.pone.0011208 Text en Kachhap 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 Kachhap, Sushant K. Rosmus, Nadine Collis, Spencer J. Kortenhorst, Madeleine S. Q. Wissing, Michel D. Hedayati, Mohammad Shabbeer, Shabana Mendonca, Janet Deangelis, Justin Marchionni, Luigi Lin, Jianqing Höti, Naseruddin Nortier, Johan W. R. DeWeese, Theodore L. Hammers, Hans Carducci, Michael A. Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor |
title | Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor |
title_full | Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor |
title_fullStr | Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor |
title_full_unstemmed | Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor |
title_short | Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor |
title_sort | downregulation of homologous recombination dna repair genes by hdac inhibition in prostate cancer is mediated through the e2f1 transcription factor |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887841/ https://www.ncbi.nlm.nih.gov/pubmed/20585447 http://dx.doi.org/10.1371/journal.pone.0011208 |
work_keys_str_mv | AT kachhapsushantk downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT rosmusnadine downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT collisspencerj downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT kortenhorstmadeleinesq downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT wissingmicheld downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT hedayatimohammad downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT shabbeershabana downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT mendoncajanet downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT deangelisjustin downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT marchionniluigi downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT linjianqing downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT hotinaseruddin downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT nortierjohanwr downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT deweesetheodorel downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT hammershans downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor AT carduccimichaela downregulationofhomologousrecombinationdnarepairgenesbyhdacinhibitioninprostatecancerismediatedthroughthee2f1transcriptionfactor |