Epigenetic corruption of VDR signalling in malignancy.
BACKGROUND
The ligand-mediated switch from binding co-repressor to co-activator complexes is central to the transcriptional actions of the vitamin D receptor (VDR) and other nuclear receptors. The capacity of deregulated co-repressors to attenuate the responsiveness of VDR signalling in cancer models was examined.


METHODS
Proliferation and gene regulation studies were undertaken in non-malignant and malignant cell line and primary models.


RESULTS
Both primary tissue models and cancer cell lines displayed a spectrum of suppressed responsiveness towards 1alpha, 25 hydroxy vitamin D3 (1alpha25(OH)2D3) which correlated with elevated co-repressor content: specifically, elevated silencing mediator of retinoid and thyroid hormone receptors/nuclear co-repressor 2 (NCoR2/SMRT) in prostate cancer cell lines and primary tumour cultures, and elevated nuclear receptor co-repressor 1 (NCoR1) in breast cancer cell lines. Interestingly, whilst the cancer cell lines frequently also displayed reduced VDR content, the primary tumour material retained and/or elevated VDR mRNA, correlated with co-repressor content. Functional approaches towards NCoR2/SMRT (siRNA) in prostate cancer cells or NCoR1 (overexpression) in non-malignant breast epithelial cells confirmed a role in suppressing VDR transcriptional and cellular actions. Targeted co-treatments of 1alpha25(OH)2D3 plus HDAC inhibitors (TSA, NaB) resulted in re-expression of antiproliferative target genes (e.g., GADD45alpha, p21(waf1/cip1)) and synergistic inhibition of proliferation.


CONCLUSIONS
These data suggest that VDR actions in solid tumours are retained, but were skewed by epigenetic mechanisms to suppress selectively antiproliferative target gene promoter responses. This molecular lesion provides a novel chemotherapy target for acceptable doses of 1alpha25(OH)2D3 plus HDAC inhibitors.
Abedin
S Asad
SA
Institute of Biomedical Research, Endocrinology and Metabolism, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, UK.
Banwell
Claire M
CM
Colston
Kay W
KW
Carlberg
Carsten
C
Campbell
Moray J
MJ
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D044127:Epigenesis, Genetic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D018167:Receptors, Calcitriol; D002117:Calcitriol