Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor

Sushant K. Kachhap, Nadine Rosmus, Spencer J. Collis, Madeleine S.Q. Kortenhorst, Michel D. Wissing, Mohammad Hedayati, Shabana Shabbeer, Janet Mendonca, Justin Deangelis, Luigi Marchionni, Jianqing Lin, Naseruddin Höti, Johan W.R. Nortier, Theodore L. Deweese, Hans Hammers, Michael A. Carducci

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere11208
JournalPLoS One
Volume5
Issue number6
DOIs
StatePublished - Aug 11 2010

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E2F1 Transcription Factor
Recombinational DNA Repair
homologous recombination
prostatic neoplasms
DNA repair
Prostatic Neoplasms
Histone Deacetylase Inhibitors
Repair
Down-Regulation
transcription factors
Genes
histone deacetylase
DNA Repair
DNA
genes
DNA Damage
DNA damage
Cells
E2F Transcription Factors
BRCA1 Gene

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Kachhap, S. K., Rosmus, N., Collis, S. J., Kortenhorst, M. S. Q., Wissing, M. D., Hedayati, M., ... Carducci, M. A. (2010). Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS One, 5(6), [e11208]. https://doi.org/10.1371/journal.pone.0011208

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.

In: PLoS One, Vol. 5, No. 6, e11208, 11.08.2010.

Research output: Contribution to journalArticle

Kachhap, SK, Rosmus, N, Collis, SJ, Kortenhorst, MSQ, Wissing, MD, Hedayati, M, Shabbeer, S, Mendonca, J, Deangelis, J, Marchionni, L, Lin, J, Höti, N, Nortier, JWR, Deweese, TL, Hammers, H & Carducci, MA 2010, 'Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor', PLoS One, vol. 5, no. 6, e11208. https://doi.org/10.1371/journal.pone.0011208
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. In: PLoS One. 2010 ; Vol. 5, No. 6.
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AU - Kortenhorst, Madeleine S.Q.

AU - Wissing, Michel D.

AU - Hedayati, Mohammad

AU - Shabbeer, Shabana

AU - Mendonca, Janet

AU - Deangelis, Justin

AU - Marchionni, Luigi

AU - Lin, Jianqing

AU - Höti, Naseruddin

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