Presentation Authors: Bichen Xue*, Shulin Wu, Libing Hu, Shahin Tabatabaei, Chin-Lee Wu, Boston, MA, Zhiyong Cheng, Blacksburg, VA, Douglas Strand, Dallas, TX, Aria Olumi, Zongwei Wang, Boston, MA
Introduction: The steroid 5-Î± reductase type 2 (SRD5A2) is critical for prostatic development and growth. Strategies to block SRD5A2 using 5-Î± reductase inhibitors (5ARI) remain a mainstay in the treatment of benign prostatic hyperplasia (BPH). However, one-third of men are resistant to 5ARI therapies. We previously have found that body mass index (BMI) can predict increased SRD5A2 promoter methylation level and decreased protein expression level. We have demonstrated that there is an â€œandrogenic to estrogenic switchâ€ when SRD5A2 is absent in the prostate gland. Here we wished to identify whether obesity-associated inflammation contributes to the androgenic to estrogenic switch in human prostate tissue.
Methods: Human prostate tissue samples came from men undergoing transurethral prostate resection. Primary prostatic stromal cells were isolated from patients undergoing prostate reduction therapy for BPH. Adipocytes and macrophages were differentiated and treated with saturated fatty acids (SFA) to induce inflammation, and SFA-free conditioned media were collected for stromal cell culturing. Protein and mRNA were extracted from stromal cells, the expression of aromatase, estrogen receptor alpha (ERÎ±), G-protein coupled estrogen receptor (GPER) and SRD5A2 was determined by Western Blot, ELISA and qPCR.
Results: In BPH patients, BMI was significantly correlated with methylation of SRD5A2 gene promoter (p < 0.05) and absence of SRD5A2 protein expression. Higher BMI was associated with higher SRD5A2 methylation levels and absence of SRD5A2 expression, as well as higher levels of aromatase and ERÎ± (P < 0.05, respectively). In primary cultured prostatic stromal cells, the levels of aromatase, ERÎ± and GPER were significantly increased, the level of SRD5A2 was significantly decreased in a dose-dependent manner when cultured with conditioned media of adipocytes or macrophages. There were much higher levels of aromatase, ERÎ± and GPER in the prostatic stromal cells when adipocytes and macrophages were pretreated with SFA.
Conclusions: Our study demonstrates for the first time that there is an androgenic to estrogenic switch, which can improve SRD5A2 methylation level and reduce SRD5A2 expression in the prostate glands of overweight patients. Associated with body weight, somatic epigenetic silencing of SRD5A2 changes the prostatic hormonal milieu, and may modulate prostatic homeostasis and growth. Targeting the estrogenic signaling may serve as an effective treatment strategy in subset of overweight BPH patients.
Source of Funding: NIH/R01 DK091353; AUA Urology Care Foundation Research Scholar Award