Epigenetic repression of transcription by the Vitamin D3 receptor in prostate cancer cells

The Journal of Steroid Biochemistry and Molecular Biology
Lyndon M GommersallMoray J Campbell

Abstract

Normal prostate epithelial cells are acutely sensitive to the antiproliferative action of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), whilst prostate cancer cell lines and primary cultures display a range of sensitivities. We hypothesised that key antiproliferative target genes of the Vitamin D receptor (VDR) were repressed by an epigenetic mechanism in 1alpha,25(OH)(2)D(3)-insensitive cells. Supportively, we found elevated nuclear receptor co-repressor and reduced VDR expression correlated with reduced sensitivity to the antiproliferative action of 1alpha,25(OH)(2)D(3). Furthermore, the growth suppressive actions of 1alpha,25(OH)(2)D(3) can be restored by co-treatment with low doses of histone deacetylation inhibitors, such as trichostatin A (TSA) to induce apoptosis. Examination of the regulation of VDR target genes revealed that co-treatment of 1alpha,25(OH)(2)D(3) plus TSA co-operatively upregulated GADD45alpha. Similarly in a primary cancer cell culture, the regulation of appeared GADD45alpha repressed. These data demonstrate that prostate cancer cells utilise a mechanism involving deacetylation to suppress the responsiveness of VDR target genes and thus ablate the antiproliferative action of 1alpha,25(OH)(2)D(3).

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Citations

Jun 5, 2014·International Journal of Cancer. Journal International Du Cancer·James L Thorne, Moray J Campbell
Apr 12, 2016·SpringerPlus·Sarah Braga Rodrigues NunesThaise Gonçalves Araújo
Jan 10, 2009·Molecular and Cellular Endocrinology·Katerina PospechovaPetr Pavek
Dec 29, 2016·The Journal of Steroid Biochemistry and Molecular Biology·Sunil J Wimalawansa

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