Age and Obesity Promote Methylation and Suppression of 5α-Reductase 2: Implications for Personalized Therapy of Benign Prostatic Hyperplasia.
OBJECTIVE
In men with symptomatic benign prostatic hyperplasia 5α-reductase inhibitors are a main modality of treatment. More than 30% of men do not respond to the therapeutic effects of 5α-reductase inhibitors. We have found that a third of adult prostate samples do not express 5α-reductase type 2 secondary to epigenetic modifications. We evaluated whether 5α-reductase type 2 expression in benign prostatic hyperplasia specimens from symptomatic men was linked to methylation of the 5α-reductase type 2 gene promoter. We also identified associations with age, obesity, cardiac risk factors and prostate specific antigen.


METHODS
Prostate samples from men undergoing transurethral prostate resection were used. We determined 5α-reductase type 2 protein expression and gene promoter methylation status by common assays. Clinical variables included age, body mass index, hypertension, hyperlipidemia, diabetes, prostate specific antigen and prostate volume. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling.


RESULTS
Body mass index and age significantly correlated with methylation of the 5α-reductase type 2 gene promoter (p <0.05) whereas prostate volume, prostate specific antigen or benign prostatic hyperplasia medication did not correlate. Methylation highly correlated with 5α-reductase protein expression (p <0.0001). In a predictive model increasing age and body mass index significantly predicted methylation status and protein expression (p <0.01).


CONCLUSIONS
Increasing age and body mass index correlate with increased 5α-reductase type 2 gene promoter methylation and decreased protein expression in men with symptomatic benign prostatic hyperplasia. These results highlight the interplay among age, obesity and gene regulation. Our findings suggest an individualized epigenetic signature for symptomatic benign prostatic hyperplasia, which may be important to choose appropriate personalized treatment options.
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Seth K
SK
Bechis
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Alexander G
AG
Otsetov
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Rongbin
R
Ge
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Zongwei
Z
Wang
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Mark G
MG
Vangel
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Chin-Lee
CL
Wu
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Shahin
S
Tabatabaei
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: Olumi.Aria@mgh.harvard.edu.
Aria F
AF
Olumi
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D009629:Person-Centered Psychotherapy; D011470:Prostatic Hyperplasia / Q000150:complications / Q000378:metabolism* / Q000628:therapy*
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C476567:steroid-5alpha-reductase type 2
5-alpha reductase inhibitors; epigenomics; lower urinary tract symptoms; obesity; prostatic hyperplasia