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Am J Pathol. 2015 Mar;185(3):870-82. doi: 10.1016/j.ajpath.2014.11.020. Epub 2015 Feb 17.

DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate.

Author information

1
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
2
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
3
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Tianjin University of Traditional Chinese Medicine, Tianjin, China.
4
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: olumi.aria@mgh.harvard.edu.

Abstract

5-α Reductase type 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Inhibition of SRD5A2 by finasteride is used commonly for the management of urinary obstruction caused by benign prostatic hyperplasia. Contrary to common belief, we have found that expression of SRD5A2 is variable and absent in one third of benign adult prostates. In human samples, absent SRD5A2 expression is associated with hypermethylation of the SRD5A2 promoter, and in vitro SRD5A2 promoter activity is suppressed by methylation. We show that methylation of SRD5A2 is regulated by DNA methyltransferase 1, and inflammatory mediators such as tumor necrosis factor α, NF-κB, and IL-6 regulate DNA methyltransferase 1 expression and thereby affect SRD5A2 promoter methylation and gene expression. Furthermore, we show that increasing age in mice and humans is associated with increased methylation of the SRD5A2 promoter and concomitantly decreased protein expression. Artificial induction of inflammation in prostate primary epithelial cells leads to hypermethylation of the SRD5A2 promoter and silencing of SRD5A2, whereas inhibition with tumor necrosis factor α inhibitor reactivates SRD5A2 expression. Therefore, expression of SRD5A2 is not static and ubiquitous in benign adult prostate tissues. Methylation and expression of SRD5A2 may be used as a gene signature to tailor therapies for more effective treatment of prostatic diseases.

PMID:
25700986
PMCID:
PMC4348471
DOI:
10.1016/j.ajpath.2014.11.020
[Indexed for MEDLINE]
Free PMC Article

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