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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 Borgmann, Kerstin

PloS one, 2010-06, Vol.5 (6), p.e11208 [Revista revisada por pares]

United States: Public Library of Science

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Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor
Autor: 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
Borgmann, Kerstin
Materias: Analysis ; Annotations ; Apoptosis ; Bioinformatics ; Biology ; Biotechnology ; BRCA1 protein ; Breast cancer ; Cancer ; Cancer genetics ; Cancer prevention ; Cell cycle ; Cell Line, Tumor ; Chemical damage ; Chromatin Immunoprecipitation ; Clinical trials ; Comet Assay ; Consortia ; Deoxyribonucleic acid ; DNA ; DNA binding proteins ; DNA Damage ; DNA microarrays ; DNA repair ; DNA Repair - genetics ; Down-Regulation - physiology ; E2F1 protein ; E2F1 Transcription Factor - physiology ; Enzymes ; Epigenetics ; Fluorescent Antibody Technique ; Gene expression ; Gene silencing ; Genes ; Genetic aspects ; Genomes ; Histone deacetylase ; Histone Deacetylases - metabolism ; Homologous recombination ; Homology ; Humans ; Inhibition ; Ionizing radiation ; Kinases ; Lung cancer ; Male ; Medical research ; Medicine ; Melanoma ; Molecular Biology/DNA Repair ; Molecular Biology/Recombination ; Oligonucleotide Array Sequence Analysis ; Oncology ; Oncology/Genitourinary Cancers ; Ontology ; Pathways ; Physicians ; Polymerase Chain Reaction ; Prevention ; Prostate cancer ; Prostatic Neoplasms - enzymology ; Prostatic Neoplasms - genetics ; Proteins ; Recombination, Genetic ; Recruitment ; Repair ; Signal transduction ; Transcription factors ; Trends ; Tumor suppressor genes
Es parte de: PloS one, 2010-06, Vol.5 (6), p.e11208
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Conceived and designed the experiments: SKK SJC MAC. Performed the experiments: SKK NR SJC MSK MDW MH SS JM JD JL. Analyzed the data: SKK NR SJC MSK MDW MH SS JM LM NH JWN TLD HJH MAC. Contributed reagents/materials/analysis tools: SKK TLD MAC. Wrote the paper: SKK.
Descripción: 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. 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. 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.
Editor: United States: Public Library of Science
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Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor

United States: Public Library of Science

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