This is another important paper. Beyond the main message that expression of SRD5A2 is not static, there is another notable finding: “inhibition with tumor necrosis factor α inhibitor reactivates SRD5A2 expression.”
Many people with PFS report reduced symptoms when ill, when supposedly tumor necrosis factor α is increased. This would suggest, contrary to what I expect, that decreasing expression of SRD5A2 improves symptoms.
To the extent that I am interpreting this correctly, this phenomenon is puzzling to me and is not consistent with my theory of the etiology of PFS. It may be consistent with the dominant theory.
There may be an alternative explanation however as tnf-a increases stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH), which stimulates the production of DHEA and may increase the substrate for 5a-reduction.
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.
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