title: DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate.
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.
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rongbin
authors.initials: R
authors.lastname: Ge
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Seth K
authors.initials: SK
authors.lastname: Bechis
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Otsetov
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shengyu
authors.initials: S
authors.lastname: Hua
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Shulin
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shahin
authors.initials: S
authors.lastname: Tabatabaei
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: olumi.aria@mgh.harvard.edu.
authors.forename: Aria F
authors.initials: AF
authors.lastname: Olumi
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases