Epigenetic corruption of VDR signalling in malignancy

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.