Bichen Xue1,2, Shulin Wu3, Christina Sharkey1, Shahin Tabatabaei3, Chin-Lee Wu3, Zhipeng Tao4, Zhiyong Cheng5, Douglas Strand6, Aria F Olumi1, Zongwei Wang7. 1. Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 2. Department of Urology, Xiangya Hospital, Xiangya Medical School, Central South University, Changsha, China. 3. Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 4. Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA. 5. Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, 32611, USA. 6. Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA. 7. Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. zwang12@bidmc.harvard.edu.
Abstract
BACKGROUND AND OBJECTIVE: Our patient cohort revealed that obesity is strongly associated with steroid-5α reductase type 2 (SRD5A2) promoter methylation and reduced protein expression. The underlying mechanism of prostatic growth in this population is poorly understood. Here we addressed the question of how obesity, inflammation, and steroid hormones affect the development of benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: We used preadipocytes, macrophages, primary human prostatic stromal cells, prostate tissues from high-fat diet-induced obese mice, and 35 prostate specimens that were collected from patients who underwent transurethral resection of the prostate (TURP). RNA was isolated and quantified with RT-PCR. Genome DNA was extracted and SRD5A2 promoter methylation was determined. Sex hormones were determined by high-performance liquid chromatography-tandem mass spectrometry. Protein was extracted and determined by ELISA test. RESULTS: In prostatic tissues with obesity, the levels of inflammatory mediators were elevated. SRD5A2 promoter methylation was promoted, but SRD5A2 expression was inhibited. Inflammatory mediators and saturated fatty acid synergistically regulated aromatase activity. Obesity promoted an androgenic to estrogenic switch in the prostate. CONCLUSIONS: Our findings suggest that obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland, which may serve as an effective strategy for alternative therapies for management of lower urinary tract symptoms associated with BPH in select individuals.
BACKGROUND AND OBJECTIVE: Our patient cohort revealed that obesity is strongly associated with steroid-5α reductase type 2 (SRD5A2) promoter methylation and reduced protein expression. The underlying mechanism of prostatic growth in this population is poorly understood. Here we addressed the question of how obesity, inflammation, and steroid hormones affect the development of benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: We used preadipocytes, macrophages, primary human prostatic stromal cells, prostate tissues from high-fat diet-induced obesemice, and 35 prostate specimens that were collected from patients who underwent transurethral resection of the prostate (TURP). RNA was isolated and quantified with RT-PCR. Genome DNA was extracted and SRD5A2 promoter methylation was determined. Sex hormones were determined by high-performance liquid chromatography-tandem mass spectrometry. Protein was extracted and determined by ELISA test. RESULTS: In prostatic tissues with obesity, the levels of inflammatory mediators were elevated. SRD5A2 promoter methylation was promoted, but SRD5A2 expression was inhibited. Inflammatory mediators and saturated fatty acid synergistically regulated aromatase activity. Obesity promoted an androgenic to estrogenic switch in the prostate. CONCLUSIONS: Our findings suggest that obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland, which may serve as an effective strategy for alternative therapies for management of lower urinary tract symptoms associated with BPH in select individuals.
Authors: Boyu Zhang; Oh-Joon Kwon; Gervaise Henry; Alicia Malewska; Xing Wei; Li Zhang; William Brinkley; Yiqun Zhang; Patricia D Castro; Mark Titus; Rui Chen; Mohammad Sayeeduddin; Ganesh V Raj; Ryan Mauck; Claus Roehrborn; Chad J Creighton; Douglas W Strand; Michael M Ittmann; Li Xin Journal: Mol Cell Date: 2016-09-01 Impact factor: 17.970
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