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Elevated NCOR1 disrupts PPARalpha/gamma signaling in prostate cancer and forms a targetable epigenetic lesion

Sebastiano Battaglia1, Orla Maguire, James L Thorne

  • 1Institute of Biomedical Research, Wolfson Drive, University of Birmingham Medical School, Edgbaston, B15 2TT, UK.

Carcinogenesis
|May 15, 2010
PubMed

Insights

Elevated nuclear corepressor 1 (NCOR1) disrupts peroxisome proliferator-activated receptor (PPAR) signaling in prostate cancer, leading to epigenetic changes. This finding offers potential diagnostic and prognostic significance for cancer patients.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Prostate cancer cell lines exhibit reduced responsiveness to ligands for vitamin D receptor, retinoic acid receptors/retinoid X receptors, and peroxisome proliferator activated receptor (PPAR)alpha/gamma.
  • This insensitivity is linked to altered messenger RNA expression of corepressors and histone-modifying enzymes, suggesting epigenetic mechanisms.
  • Elevated levels of nuclear corepressor 1 (NCOR1) and nuclear corepressor 2 were observed in prostate cancer cell lines compared to non-malignant cells.

Purpose of the Study:

  • To investigate the role of epigenetic events, specifically corepressor involvement, in the loss of anti-proliferative responsiveness in prostate cancer.
  • To elucidate the mechanism by which elevated NCOR1 impacts PPARalpha/gamma signaling and target gene regulation.
  • To explore the potential of NCOR1-PPARalpha/gamma interactions as diagnostic and prognostic markers in prostate cancer.

Main Methods:

  • Messenger RNA expression analysis of corepressors and histone-modifying enzymes.
  • Knockdown of NCOR1 to assess its effect on target gene expression and anti-proliferative sensitivity.
  • Combination treatment with histone deacetylases inhibitor (HDACi) and PPARalpha/gamma ligands.
  • Microarray analysis to identify genes regulated by PPARalpha/gamma activation and HDAC inhibition.
  • Quantitative real-time polymerase chain reaction and chromatin immunoprecipitation assays.
  • Principal component and partial correlation analyses in prostate cancer samples.

Main Results:

  • Knockdown of NCOR1 significantly increased basal expression of target genes, including CDKN1A.
  • Both HDAC inhibition and NCOR1 knockdown enhanced anti-proliferative sensitivity to PPARalpha/gamma ligands.
  • Elevated NCOR1 distorted PPARalpha/gamma target genes involved in cell cycle control (e.g., CDKN1A, TGFBRAP1).
  • Quantitative real-time polymerase chain reaction and chromatin immunoprecipitation confirmed NCOR1's disruption of PPARalpha/gamma regulation.
  • Prostate cancer samples showed significant interdependent relationships between NCOR1, PPARalpha/gamma, and target genes.

Conclusions:

  • Elevated NCOR1 selectively distorts the actions of PPARalpha/gamma in prostate cancer.
  • This distortion represents a potential epigenetic lesion with diagnostic and prognostic significance.
  • Targeting NCOR1 or HDACs may restore sensitivity to PPARalpha/gamma ligands, offering therapeutic potential.

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