Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2

Abstract

Benign prostatic hyperplasia is the most common proliferative abnormality of the prostate. All men experience some prostatic growth as they age, but the rate of growth varies among individuals. Steroid 5α-reductase 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Previous work indicates that one-third of adult prostatic samples do not express SRD5A2, secondary to epigenetic modifications. Here we show that the level of oestradiol is dramatically elevated, concomitant with significant upregulation of oestrogen response genes, in prostatic samples with methylation at the SRD5A2 promoter. The phosphorylation of oestrogen receptor-α in prostatic stroma is upregulated when SRD5A2 expression is absent. We show that tumour necrosis factor (TNF)-α suppresses SRD5A2 mRNA and protein expression, and simultaneously promotes expression of aromatase, the enzyme responsible for conversion of testosterone to oestradiol. Concomitant suppression of SRD5A2 and treatment with TNF-α synergistically upregulate the aromatase levels. The data suggest that, in the absence of prostatic SRD5A2, there is an androgenic to oestrogenic switch. These findings have broad implications for choosing appropriate classes of medications for the management of benign and malignant prostatic diseases.

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy

“…An explanation could be that SRD5A2 promoter hypermethylation causes the absence of SRD5A2 expression, and an androgenic to estrogenic switch in prostate tissue. This hypothesis is supported by our recent studies and others [17,[33][34][35]. In BPH tissues, we showed that the level of estradiol is dramatically elevated in prostatic samples with methylation of the SRD5A2 promoter, a condition that favors an estrogenic, as opposed to an androgenic, milieu in the prostate.…”

“…In benign prostatic tissue, expression of SRD5A2 protein is variable and negatively correlated with methylation of the SRD5A2 promoter. Our recent studies show that 30% of adult prostates without malignancy do not express the SRD5A2 gene or protein, and that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene [15][16][17]. In this study, we tested SRD5A2 promoter methylation of 42 prostatic specimens and 12 metastatic biopsies and found significant hypermethylation of SRD5A2 promoter region for CRPC compared with benign prostatic specimens.…”

“…IHC was completed as previously described [16,17]. More detail is described in the Supplementary Information.…”

Integrative genomic, transcriptomic, and epigenomic analyses of benign prostatic hyperplasia reveal new options for therapy

“…We therefore performed integrative analysis using transcriptional and methylation profiling, and identified two distinct BPH subtypes ( Figure 3A and Tables S6-7), supporting robust biologically distinct subgroups across different data types. To validate distinct subtypes in BPH, we tested our signature via k-means clustering in two independent cohorts 20,21 , and identified nearly identical subgroups (Figures 3C, 3E and Table S8), further supporting the robustness of these subgroups across data types and sources. We then examined the molecular and clinical features of these two groups.…”

“…Histologically, BPH is characterized as the overgrowth of stromal and epithelial cells, and it occurs in the transitional zone of prostate 1 . Currently, many BPH studies have focused on risk factors of BPH 12,13,14,15 , while the underlying molecular features of BPH remain understudied 3,9,16,17,18,19 and molecular data is relatively scarce 20,21 . Moreover, BPH has been described as "the most common benign tumor in men", and is commonly referred to as an adenoma, but unlike many malignant 22,23 and benign neoplasms 24,25,26 , it is unknown whether BPH is a neoplastic process 3,7,18,19,20 .…”