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. MATERIALS AND 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. CONCLUSION: 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.
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. MATERIALS AND 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. CONCLUSION: 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.
Authors: Charles Giardina; James P Madigan; Cassandra A Godman Tierney; Bruce M Brenner; Daniel W Rosenberg Journal: Carcinogenesis Date: 2011-12-16 Impact factor: 4.944
Authors: Aristeidis G Vaiopoulos; Ioannis D Kostakis; Kalliopi Ch Athanasoula; Athanasios G Papavassiliou Journal: Cell Mol Life Sci Date: 2012-04-19 Impact factor: 9.261
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Authors: Negar Khazan; Kyu Kwang Kim; Jeanne N Hansen; Niloy A Singh; Taylor Moore; Cameron W A Snyder; Ravina Pandita; Myla Strawderman; Michiko Fujihara; Yuta Takamura; Ye Jian; Nicholas Battaglia; Naohiro Yano; Yuki Teramoto; Leggy A Arnold; Russell Hopson; Keshav Kishor; Sneha Nayak; Debasmita Ojha; Ashoke Sharon; John M Ashton; Jian Wang; Michael T Milano; Hiroshi Miyamoto; David C Linehan; Scott A Gerber; Nada Kawar; Ajay P Singh; Erdem D Tabdanov; Nikolay V Dokholyan; Hiroki Kakuta; Peter W Jurutka; Nina F Schor; Rachael B Rowswell-Turner; Rakesh K Singh; Richard G Moore Journal: J Med Chem Date: 2022-04-11 Impact factor: 8.039