Antiproliferative Signalling by 1, 25(OH)2D3in Prostate and Breast Cancer Is Suppressed by a Mechanism Involving Histone Deacetylation

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Abstract
Breast and prostate cancer are leading causes of cancer death in the Western world. Hormone ablation is the primary therapy for invasive disease, but the tumour often recurs in an androgen or oestrogen receptor negative form for which novel therapies are sought urgently. The vitamin D receptor (VDR)may provide an important alternative therapeutic target. However, cancer cell line models from these tissues display a range of sensitivities to the antiproliferativeffects of 1α,25dihydroxyvitamin D3(1α,25(OH)2D3). The reason for apparent 1α,25(OH)2D3insensitivity is currently unknown and we have investigatedepigenetic mechanisms that may suppress the transcriptional activity of the VDR. Nuclear co-repressors have associated histone deacetylase (HDAC) activity, which keeps chromatin in a closed, transcriptionally silent state. We have found that the aggressive cancer cell lines with relative insensitivity to 1α,25(OH)2D3have elevated nuclear co-repressor levels. For example,PC-3 prostate cancer cells have a significant 1.8-fold elevation in the co-repressor SMRT compared to normal epithelial cells (P2D3resistance. Consistent with this, we have shown that combining a low dose of HDAC inhibitor Trichostatin A (15 nM TSA) with1α,25(OH)2D3(100 nM) synergistically inhibits the proliferation of PC-3 prostateand MDA-MB-231 breast cancer cell lines. The inhibition of proliferationwas potentiated further by treating cells with 19-nor-hexafluoride vitamin D3analogues instead of 1α,25(OH)2D3, plus TSA. For example, the combinationof 1α,25(OH)2D3and TSA-inhibited MDA-MB-231 cell proliferation by 38% (€5%), whereas Ro26-2198 (1α,25-(OH)2-16,23Z-diene-26,27-F6-19-nor-D3)and TSA inhibited growth by 62% (€2%). Therapeutically the hypercalcaemicside effects associated with 1α,25(OH)2D3could be minimized by combininglow doses of potent 1α,25(OH)2D3analogues with HDAC inhibitors as a novelanticancer regime for hormone-insensitive prostate and breast cancer.