Epigenetic repression of transcription by the Vitamin D3 receptor in prostate cancer cells.
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).
Gommersall
Lyndon M
LM
Department of Medicine, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TH, UK.
Khanim
Farhat L
FL
Peehl
Donna M
DM
Doherty
Alan H
AH
Campbell
Moray J
MJ
D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D051548:Histone Acetyltransferases; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018167:Receptors, Calcitriol / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology*
D017931:DNA Primers; D018167:Receptors, Calcitriol; D000123:Acetyltransferases; D051548:Histone Acetyltransferases