The relevance of estrogen receptor-β expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment

In the prostate, estrogen receptor β (ERβ), the preferred receptor for phytoestrogens, has features of a tumor suppressor. To investigate the mechanisms underlying the beneficial effects on prostate cancer of histone deacetylase inhibitor valproic acid (VPA) and phytoestrogen tectorigenin, we analyzed the expression of ERβ after tectorigenin or VPA treatment. For further functional analysis, we knocked down ERβ expression by RNA interference. LNCaP prostate cancer cells were treated with 5 mmol/L VPA or 100 μmol/L tectorigenin and transfected with small interfering RNA (siRNA) against ERβ. Control transfections were done with luciferase (LUC) siRNA. Expression of ERβ was assessed by Western blot. mRNA expression was quantitated by real-time reverse transcription-PCR. Expression of ERβ mRNA and protein markedly increased after VPA or tectorigenin treatment. When ERβ was knocked down by siRNA, the expression of prostate-derived Ets factor, prostate-specific antigen, prostate cancer–specific indicator gene DD3 PCA3 , insulin-like growth factor-1 receptor, the catalytic subunit of the telomerase, and ERα was up-regulated and the tectorigenin effects were abrogated. ERβ levels were diminished in prostate cancer and loss of ERβ was associated with proliferation. Here, we show that siRNA-mediated knockdown of ERβ increases the expression of genes highly relevant to tumor cell proliferation. In addition, we show that one prominent result of treatment with VPA or tectorigenin is the up-regulation of ERβ resulting in antiproliferative effects. Thus, these drugs, by restoring the regulatory function of ERβ in tumor cells, could become useful in the intervention of prostate cancer. [Mol Cancer Ther 2007;6(10):2626–33]