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Epigenetic corruption of VDR signalling in malignancy

S Asad Abedin1, Claire M Banwell, Kay W Colston

  • 1Institute of Biomedical Research, Endocrinology and Metabolism, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, UK.

Anticancer Research
|August 5, 2006
PubMed
Abstract

Insights

Elevated co-repressors suppress vitamin D receptor (VDR) signaling in cancer. Combining VDR agonists with HDAC inhibitors restores VDR function and inhibits cancer cell proliferation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • The vitamin D receptor (VDR) regulates gene transcription through interactions with co-activator and co-repressor complexes.
  • Deregulation of co-repressors can impair VDR signaling, particularly in the context of cancer.

Purpose of the Study:

  • To investigate the role of deregulated co-repressors in attenuating VDR signaling responsiveness in cancer models.
  • To explore the potential of targeting co-repressors and VDR signaling for cancer therapy.

Main Methods:

  • Proliferation and gene regulation studies were conducted in non-malignant and malignant cell lines, as well as primary tissue models.
  • Functional assays included siRNA-mediated knockdown of co-repressors and overexpression studies.
  • Co-treatments with VDR agonists and HDAC inhibitors were performed.

Main Results:

  • Suppressed VDR responsiveness in cancer models correlated with increased levels of specific co-repressors (NCoR2/SMRT in prostate cancer, NCoR1 in breast cancer).
  • While some cancer cell lines showed reduced VDR levels, primary tumors often maintained or increased VDR mRNA, inversely correlating with co-repressor levels.
  • Functional studies confirmed the suppressive role of NCoR2/SMRT and NCoR1 in VDR-mediated gene regulation and cellular actions.
  • Combination therapy with 1alpha,25-dihydroxyvitamin D3 and HDAC inhibitors reactivated antiproliferative genes and synergistically inhibited proliferation.

Conclusions:

  • VDR signaling in solid tumors is retained but epigenetically modified to suppress antiproliferative gene responses.
  • This molecular alteration presents a therapeutic target, suggesting that combined treatment with VDR agonists and HDAC inhibitors can overcome VDR suppression in cancer.

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