Gommersall Lyndon M, Khanim Farhat L, Peehl Donna M, Doherty Alan H, Campbell Moray J
Department of Medicine, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TH, UK.
J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):251-6. doi: 10.1016/j.jsbmb.2004.03.080.
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).
正常前列腺上皮细胞对1α,25 - 二羟基维生素D(3)（1α,25(OH)₂D₃）的抗增殖作用极为敏感，而前列腺癌细胞系和原代培养细胞则表现出不同程度的敏感性。我们推测，在对1α,25(OH)₂D₃不敏感的细胞中，维生素D受体（VDR）的关键抗增殖靶基因通过表观遗传机制受到抑制。支持这一推测的是，我们发现核受体共抑制因子水平升高和VDR表达降低与对1α,25(OH)₂D₃抗增殖作用的敏感性降低相关。此外，低剂量组蛋白去乙酰化抑制剂（如曲古抑菌素A（TSA））联合处理可恢复1α,25(OH)₂D₃的生长抑制作用，诱导细胞凋亡。对VDR靶基因调控的研究表明，1α,25(OH)₂D₃与TSA联合处理协同上调了GADD45α。同样，在原代癌细胞培养中，GADD45α的调控也受到抑制。这些数据表明，前列腺癌细胞利用一种涉及去乙酰化的机制来抑制VDR靶基因的反应性，从而消除1α,25(OH)₂D₃的抗增殖作用。
