# SRD5A2 as a Marker of Resistance to 5ARI Therapy

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $364,809

## Abstract

PROJECT SUMMARY:
 Over 90% of adult males develop lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction
by age 80, rendering benign prostatic hyperplasia (BPH) the most common proliferative abnormality in humans.
LUTS secondary to BPH negatively impact the quality of life of 210 million men globally, accounting for significant
life years lost. In this study we propose to clinically evaluate the mechanisms of resistance to 5α-reductase
inhibitor, finasteride, one of the more common drugs used to manage BPH and associated LUTS.
 Ongoing work in our lab has focused on steroid 5α-reductase 2 (SRD5A2, aka: 5α-reductase 2 [5AR2]), the
enzyme responsible for prostatic development and growth. Our investigations have revealed that expression of
SRD5A2 is variable, and in fact, 30% of men do not express SRD5A2 in prostate tissues. In previous work, we
showed that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes
associated with methylation of the promoter region of the SRD5A2 gene. Our studies indicate that (1)
methylation of the SRDA2 is regulated by direct binding of the DNA-methyl transferase 1 (DNMT1) protein to
the SRD5A2 promoter; (2) the inflammatory mediators TNF-α, NF-kB, and IL-6 regulate DNMT1 binding and
subsequent methylation of the SRD5A2 promoter region; (3) clinical conditions associated with increased
inflammation, age, and obesity, are associated with decreased expression of SRD5A via epigenetic
modification; (4) in the absence of prostatic SRD5A2, where androgenic pathways are blocked, alternate
estrogenic pathways are upregulated, leading to an androgenic-to-estrogenic switch in the prostate gland, thus
creating alternate pathways for prostatic growth. Therefore, we hypothesize that absence of SRD5A2 as a
result of somatic methylation is directly responsible for lack of sensitivity to 5ARI therapy in men with
BPH. To demonstrate the clinical significance of epigenetic changes to SRD5A2 and confirm its role in
regulating sensitivity to 5ARI treatment, we propose the following aims: Specific Aim 1: To assess the role of
5-AR2 expression in the development of resistance to 5-ARI therapy. Specific Aim 2: To demonstrate that
SRD5A2 methylation turns on estrogen pathways and affects sensitivity to 5ARI therapies in men with BPH.
Specific Aim 3: To determine that prostatic inflammation is associated with methylation of SRD5A2 promoter.
Our findings have broad implications for the development of predictive biomarker assays that can be used to
evaluate resistance to BPH-related therapies and allow clinicians to select alternate therapies for managing the
most common proliferative disorder affecting men worldwide.

## Key facts

- **NIH application ID:** 10148769
- **Project number:** 5R01DK124502-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Aria F Olumi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,809
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148769

## Citation

> US National Institutes of Health, RePORTER application 10148769, SRD5A2 as a Marker of Resistance to 5ARI Therapy (5R01DK124502-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148769. Licensed CC0.

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