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

Zongwei Wang, Libing Hu, Keyan Salari, Seth Bechis, Rongbin Ge, Shulin Wu, Cyrus Rassoulian, Jonathan Pham, Chin Lee Wu, Shahin Tabatabaei, Douglas W. Strand, Aria F. Olumi

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)457-467
Number of pages11
JournalJournal of Pathology
Volume243
Issue number4
DOIs
StatePublished - Dec 1 2017

Fingerprint

Epigenomics
Prostate
Oxidoreductases
Steroids
Aromatase
Estradiol
Up-Regulation
Tumor Necrosis Factor-alpha
Prostatic Diseases
Prostatic Hyperplasia
Enzymes
Growth
Growth and Development
Estrogen Receptors
Methylation
Testosterone
Estrogens
Phosphorylation
Messenger RNA
Genes

Keywords

  • androgenic to oestrogenic switch
  • epigenetic silencing
  • methylation
  • prostate
  • steroid 5α-reductase 2

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2. / Wang, Zongwei; Hu, Libing; Salari, Keyan; Bechis, Seth; Ge, Rongbin; Wu, Shulin; Rassoulian, Cyrus; Pham, Jonathan; Wu, Chin Lee; Tabatabaei, Shahin; Strand, Douglas W.; Olumi, Aria F.

In: Journal of Pathology, Vol. 243, No. 4, 01.12.2017, p. 457-467.

Research output: Contribution to journalArticle

Wang, Z, Hu, L, Salari, K, Bechis, S, Ge, R, Wu, S, Rassoulian, C, Pham, J, Wu, CL, Tabatabaei, S, Strand, DW & Olumi, AF 2017, 'Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2', Journal of Pathology, vol. 243, no. 4, pp. 457-467. https://doi.org/10.1002/path.4985
Wang, Zongwei ; Hu, Libing ; Salari, Keyan ; Bechis, Seth ; Ge, Rongbin ; Wu, Shulin ; Rassoulian, Cyrus ; Pham, Jonathan ; Wu, Chin Lee ; Tabatabaei, Shahin ; Strand, Douglas W. ; Olumi, Aria F. / Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2. In: Journal of Pathology. 2017 ; Vol. 243, No. 4. pp. 457-467.
@article{796a91c5ee5b448083e34247d8951c2e,
title = "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.",
keywords = "androgenic to oestrogenic switch, epigenetic silencing, methylation, prostate, steroid 5α-reductase 2",
author = "Zongwei Wang and Libing Hu and Keyan Salari and Seth Bechis and Rongbin Ge and Shulin Wu and Cyrus Rassoulian and Jonathan Pham and Wu, {Chin Lee} and Shahin Tabatabaei and Strand, {Douglas W.} and Olumi, {Aria F.}",
year = "2017",
month = "12",
day = "1",
doi = "10.1002/path.4985",
language = "English (US)",
volume = "243",
pages = "457--467",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley and Sons Ltd",
number = "4",

}

TY - JOUR

T1 - Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2

AU - Wang, Zongwei

AU - Hu, Libing

AU - Salari, Keyan

AU - Bechis, Seth

AU - Ge, Rongbin

AU - Wu, Shulin

AU - Rassoulian, Cyrus

AU - Pham, Jonathan

AU - Wu, Chin Lee

AU - Tabatabaei, Shahin

AU - Strand, Douglas W.

AU - Olumi, Aria F.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - androgenic to oestrogenic switch

KW - epigenetic silencing

KW - methylation

KW - prostate

KW - steroid 5α-reductase 2

UR - http://www.scopus.com/inward/record.url?scp=85034252228&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85034252228&partnerID=8YFLogxK

U2 - 10.1002/path.4985

DO - 10.1002/path.4985

M3 - Article

C2 - 28940538

AN - SCOPUS:85034252228

VL - 243

SP - 457

EP - 467

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 4

ER -