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Absence of 5-alpha Reductase 2 in Benign Human Adult Prostates
Rongbin Ge, M.D, PhD., Zongwei Wang, PhD, Chin-Lee Wu, M.D, PhD., Shahin Tabatabaei, M.D., Aria F. Olumi, M.D..
MGH, Boston, MA, USA.
BACKGROUND:
5-alpha reductase type 2 (5-AR2), an enzyme that is critical for prostatic development and growth, is utilized as an inhibitory target by Finasteride for patients with BPH. One third of men with obstructive lower urinary tract symptoms from BPH are resistant to the therapeutic effects of Finasteride. We have found that many adult human benign prostate tissues do not express 5-AR2. Since the 5-AR2 promoter region contains a CpG island, we hypothesized that somatic methylation of the promoter region may account for absence of 5-AR2 expression.
METHODS:
Benign transition zone prostatic tissues from 42 radical prostatectomies were used. Expression of 5-AR2 was analyzed by immunohistochemistry (protein) and RT-PCR (mRNA). Methylation of 5-AR2 promoter region was assessed using methyl-specific RT-PCR.
RESULTS:
For the initial immunohistochemical (IHC) assessment 21 benign transition zone prostate samples revealed that 29% (6/21) did not express the 5-AR2 protein. 5-AR2 contains a rich CpG island in its promoter region, and immortalized prostate epithelial cells which do not express 5-AR2 protein, were heavily methylated in the promoter region of 5-AR2 gene. In human prostate samples that were available for PCR analysis, 44% (8/18) demonstrated low 5-AR2 RNA expression, and 38% (7/18) of the prostate samples were methylated in the 5-AR2's promoter region. We found significant correlation between methylation of 5-AR2 promoter region and expression of 5-AR2 protein (Chi square, p=0.011). To determine whether there is any intraprostatic variability, benign tissue from different portions of transition zone from four different patients were evaluated. We found concordant expression of 5-AR2 and methylation of 5-AR2 by IHC and methyl-specific RT-PCR analysis.
CONCLUSIONS:
Expression of 5-AR-2 is absent in one-third of adult prostatic transition zones. We believe that somatic methylation of 5-AR2 promoter accounts for silencing of 5-AR2 expression. Absent 5-AR2 in adult prostates has implications for using 5-AR2 inhibitors for management of BPH and chemopreventive strategies for prostate cancer.
Funding: NIH/R01: DK091353-01
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