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

In the prostate, estrogen receptor beta (ERbeta), 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 ERbeta after tectorigenin or VPA treatment. For further functional analysis, we knocked down ERbeta expression by RNA interference. LNCaP prostate cancer cells were treated with 5 mmol/L VPA or 100 micromol/L tectorigenin and transfected with small interfering RNA (siRNA) against ERbeta. Control transfections were done with luciferase (LUC) siRNA. Expression of ERbeta was assessed by Western blot. mRNA expression was quantitated by real-time reverse transcription-PCR. Expression of ERbeta mRNA and protein markedly increased after VPA or tectorigenin treatment. When ERbeta 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 ERalpha was up-regulated and the tectorigenin effects were abrogated. ERbeta levels were diminished in prostate cancer and loss of ERbeta was associated with proliferation. Here, we show that siRNA-mediated knockdown of ERbeta 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 ERbeta resulting in antiproliferative effects. Thus, these drugs, by restoring the regulatory function of ERbeta in tumor cells, could become useful in the intervention of prostate cancer.