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

Abstract

In the prostate, estrogen receptor B (ERB), 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 ERB after tectorigenin or VPA treatment. For further functional analysis, we knocked down ERB expression by RNA interference. LNCaP prostate cancer cells were treated with 5 mmol/L VPA or 100 Mmol/L tectorigenin and transfected with small interfering RNA (siRNA) against ERB. Control transfections were done with luciferase (LUC) siRNA. Expression of ERB was assessed by Western blot. mRNA expression was quantitated by real-time reverse transcription-PCR. Expression of ERB mRNA and protein markedly increased after VPA or tectorigenin treatment. When ERB was knocked down by siRNA, the expression of prostatederived 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 ERA was up-regulated and the tectorigenin effects were abrogated. ERB levels were diminished in prostate cancer and loss of ERB was associated with proliferation. Here, we show that siRNA-mediated knockdown of ERB 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 ERB resulting in antiproliferative effects. Thus, these drugs, by restoring the regulatory function of ERB in tumor cells, could become useful in the intervention of prostate cancer. [Mol Cancer Ther 2007;6(10):2626 -33]

Estrogen receptor beta in prostate cancer: friend or foe?

“…The traditional Japanese diet contains high levels of dietary phytoestrogens, which have been shown in prostate cancer cell lines to upregulate ERB activity resulting in decreased expression of AR (Thelen et al 2005, Stettner et al 2007) and induction of G1-cell cycle block (Shen et al 2000). In rat models, phytoestrogens can induce prostate epithelial cell apoptosis (Attia & Ederveen 2012), thereby demonstrating protective effects against prostate cancer.…”

Expression of prostate stem cell antigen is downregulated during flavonoid-induced cytotoxicity in prostate cancer cells

“…In prostate cancer, numerous biomarkers have been identified, including PSA, prostate-specific membrane antigen, PSCA, early prostate cancer antigen, B7-H3, chromogranin A, α-methylacyl coenzyme A racemase, glutathione S-transferase P1 (GSTP1), sarcosine, caveolin-1, TMPRSS2-ERG, Ki-67, prostate cancer antigen 3 (PCA3) and disabled homolog 2-interacting protein (35). Previous studies have demonstrated that a number of these biomarkers, including PSA, GSTP1, Ki-67 and PCA3, were the targets by which flavonoids exerted anticancer effects in prostate cancer (36)(37)(38)(39). Using human xenografts grown in mice with severe combined immunodeficiency, it has also been demonstrated that anti-PSCA monoclonal antibodies inhibited the growth and metastasis of tumors (40), thus indicating that PSCA may be an immunotherapeutic target in the treatment of prostate cancer (40,41).…”

Estrogen Receptors: Their Actions and Functional Roles in Health and Disease

“…Treatment of LNCap cells with the histone deacetylase inhibitor valproic acid (VPA) and the phytoestrogen tectorigenin, respectively, caused a significant increase in ERβ expression, accompanied by an antiproliferative effect. In contrast, silencing of ERβ expression resulted in resumed LNCap proliferation including upregulation of genes involved in cell cycle regulation [475].…”