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  • Original Paper
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Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells

Oncogene volume 23, pages 6712–6725 (2004)Cite this article

Abstract

We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of nonmalignant and malignant cell lines and primary cultures, and found frequently elevated SMRT corepressor mRNA expression often associated with reduced sensitivity to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (P<0.05). Similarly, 10/15 primary tumour cultures (including three matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Corepressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1α,25(OH)2D3 can be ‘restored’ by cotreatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 nM) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses, we undertook gene expression studies in PC-3 cells after cotreatment of 1α,25(OH)2D3 plus TSA after 6 h. Examination of known VDR target genes and cDNA microarray analyses revealed cotreatment of 1α,25(OH)2D3 plus TSA cooperatively upregulated eight (out of 1176) genes, including MAPK-APK2 and GADD45α. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently, we knocked down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45α induction by 1α,25(OH)2D3 alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45α was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1α,25(OH)2D3-insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors.

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Acknowledgements

This work was supported in part by the Cancer Research Fund, under Interagency Agreement #97-12013 (University of California, Davis Contract #98-00924 V) with the Department of Health Services, Cancer Research Section. Mention of trade name, proprietary product or specific equipment does not constitute a guaranty or warranty by the Department of Health Services, nor does it imply approval to the exclusion of other products. The views expressed herein represent those of the authors and do not necessarily represent the position of the State of California, Department of Health Services (DMP). This work was supported in part by grants from the United Birmingham Hospitals Endowment Fund, Prostate Research Campaign UK, and National Cancer Research Institute Prostate Research Cancer Collaborative, UK (MJC).

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  1. Farhat L Khanim

    Present address: School of Biosciences, The University of Birmingham, Birmingham, B15 2TT, UK

  2. Farhat L Khanim and Lyndon M Gommersall: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, B15 2TH, Edgbaston, UK

    Farhat L Khanim, Lyndon M Gommersall, Victoria HJ Wood, Kirsty L Smith, Leire Montalvo, Paul M Stewart & Moray J Campbell

  2. Division of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, B15 2TH, Edgbaston, UK

    Laura P O'Neill & Bryan M Turner

  3. Department of Urology, Stanford University School of Medicine, Stanford, 94305-5118, CA, USA

    Yue Xu & Donna M Peehl

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Khanim, F., Gommersall, L., Wood, V. et al. Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells. Oncogene 23, 6712–6725 (2004). https://doi.org/10.1038/sj.onc.1207772

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