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Androgenic to Estrogenic Switch in Human Adult Prostate Gland as a result of Epigenetic Silencing of Steroid 5-alpha Reductase 2
Zongwei Wang, PhD1, Libing Hu, MD1, Rongbin Ge, PhD, MD2, Keyan Salari, MD1, Shulin Wu, MD1, Seth Bechis, MD1, Cyrus Rassoulian, N/A1, Jonathan Pham, MD candidate1, Chin-Lee Wu, PhD, MD3, Shahin Tabetabaei, MD1, Douglas Strand, PhD4, Aria Olumi, MD1.
1Massachusetts General Hospital, Boston, MA, USA, 2University of Massachusetts Medical Center, Worcester, MA, USA, 3Massachusetts General Hospital, Belmont, MA, USA, 4UT Southwestern Medical Center, Dallas, TX, USA.

BACKGROUND:
The steroid 5-α reductase type 2 (SRD5A2) is critical for prostatic development and growth. Strategies to block SRD5A2 using 5-alpha 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 showed that expression of SRD5A2 is not static, since epigenetic modulations by DNA methyltransferase and pro-inflammatory cytokines somatically silence SRD5A2 during adulthood. Here we wished to identify whether absence of prostatic SRD5A2, when androgenic pathways are blocked, leads to modification of alternate hormonal pathways.
METHODS:
Prostatic samples were obtained from patients with symptomatic BPH undergoing transurethral resection of prostate (TURP) surgery. Prostatic protein expression of SRD5A2, androgen receptor (AR), estrogen receptor (ER) subunits, and aromatase were determined by Western blot, immunohistochemistry (IHC), and ELISA assays. Prostatic levels of testosterone (T), dihydrotestosterone (DHT), estradiol (E) were measured by HPLC-MS. In in vitro study, primary prostatic stroma cells and epithelial cells BPE and BPH-1 were cultured and treated with TNF-α, and the expression of aromatase were determined by qPCR and ELISA.
RESULTS:
In prostate specimens that were methylated at the SRD5A2 promoter locus, estrogen response genes are among the most significantly upregulated genes in prostate samples that are methylated at the SRD5A2 promoter locus. The levels of T, E and aromatase were significantly upregulated, while DHT was significantly decreased. The ratio of T/E was significantly lower. DHT was inversely correlated with T levels, and aromatase was negatively correlated with DHT. Absence of SRD5A2 significantly upregulated the phosphorylation of ERα (pERα), but did not significantly affect the levels of total ERα, total ERβ or pERβ. In primary prostatic stromal cells, the aromatase levels were significantly increased with TNF-α treatment alone or when expression of SRD5A2 was suppressed by siRNA transfection. Treatment of prostatic epithelial BPH-1 cells with TNF-α did not change the androgenic or estrogenic signalling, but the aromatase levels in stromal cells were significantly upregulated when treated with TNF-α and cultured in BPH-1 conditioned media.
CONCLUSIONS:
Our study demonstrates for the first time that there is an androgenic to estrogenic switch when SRD5A2 is absent in the prostate gland. Somatic epigenetic silencing of SRD5A2 changes the prostatic hormonal milieu, and may modulate prostatic homeostasis and growth. ER modifiers may prove to be better therapeutic options in carefully selected patients who lack SRD5A2 expression for management of prostatic diseases.
Grant support: NIH/R01 DK091353


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