Age and Obesity Promote Methylation and Suppression of 5α-Reductase 2: Implications for Personalized Therapy of Benign Prostatic Hyperplasia

Abstract

Purpose: 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.

Materials and 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.

Keywords: 5-alpha reductase inhibitors; epigenomics; lower urinary tract symptoms; obesity; prostatic hyperplasia.

Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Mechanism of 5AR2 suppression by DNA methylation. (A) DNA methylation adds a methyl group (star) at the carbon-5 position of cytosine residues in CG dinucleotides. (B) In unmethylated DNA (blue CG dinucleotides), chromatin is uncondensed and transcription factors (TF) can bind the gene promoter region, enabling gene expression. (C–D) DNA methylation (red CG dinucleotides with stars) attracts methylated DNA-binding proteins and histone deacetylase complexes (horizontal ovals and diamonds) to form condensed, inactive chromatin that prevents TF binding and silences gene expression (from ref).

Figure 2

Methylation status of the 5AR2 promoter predicts protein expression. Plot shows probability of protein expression with 95% confidence intervals shown.

Figure 3

A. Age is a statistically significant predictor of methylation status, with positive methylation status correlating with increased age. Overall mean is shown by the horizontal line. Box plots show 25th to 75th interquartile range and median (horizontal line), whiskers show 10% and 90% quantiles. Wilcoxon rank sum, p=0.020. B. Body mass index (BMI) is a statistically significant predictor of methylation status, with positive methylation status correlating with increased BMI. Overall mean is shown by the horizontal line. Box plots show 25th to 75th interquartile range and median (horizontal line), whiskers show 10% and 90% quantiles. Wilcoxon rank sum, p=0.028.

Figure 3

A. Age is a statistically significant predictor of methylation status, with positive methylation status correlating with increased age. Overall mean is shown by the horizontal line. Box plots show 25th to 75th interquartile range and median (horizontal line), whiskers show 10% and 90% quantiles. Wilcoxon rank sum, p=0.020. B. Body mass index (BMI) is a statistically significant predictor of methylation status, with positive methylation status correlating with increased BMI. Overall mean is shown by the horizontal line. Box plots show 25th to 75th interquartile range and median (horizontal line), whiskers show 10% and 90% quantiles. Wilcoxon rank sum, p=0.028.

Figure 4

ROC curves for BMI, age, and both as predictors of 5AR2 methylation status. Age AUC 0.64 (95% CI [0.53, 0.76]); BMI AUC 0.68 ([0.57, 0.79]), Age + BMI AUC 0.72 ([0.62, 0.83]).