SRD5A2 as a Marker of Resistance to 5ARI Therapy

项目概要： 超过90%的成年男性发生继发于膀胱出口梗阻的下尿路症状（LUTS） 到80岁，使良性前列腺增生（BPH）成为人类最常见的增生性异常。 继发于BPH的LUTS对全球2.1亿男性的生活质量产生了负面影响，占全球人口的 失去的生命岁月在这项研究中，我们建议临床评估耐药机制5α-还原酶 抑制剂，芬鲁肽，用于管理BPH和相关LUTS的较常见药物之一。 我们实验室正在进行的工作集中在类固醇5α-还原酶2（SRD 5A 2，又名：5α-还原酶2 [5AR 2]）， 负责前列腺发育和生长的酶。我们的调查显示， SRD 5A 2是可变的，事实上，30%的男性在前列腺组织中不表达SRD 5A 2。在以前的工作中，我们 表明成年期SRD 5A 2的体细胞抑制依赖于表观遗传变化 与SRD 5A 2基因启动子区甲基化相关。研究表明：（1） SRDA 2的甲基化通过DNA甲基转移酶1（DNMT 1）蛋白直接结合到 SRD 5A 2启动子;（2）炎症介质TNF-α、NF-kB和IL-6调节DNMT 1结合， SRD 5A 2启动子区域随后的甲基化;（3）与增加的 炎症、年龄和肥胖与SRD 5A表达的降低有关， （4）在前列腺SRD 5A 2缺失的情况下，雄激素途径被阻断， 雌激素途径被上调，导致前列腺中雄激素到雌激素的转换， 为前列腺生长创造了另一条途径。因此，我们假设SRD 5A 2的缺失是一种 体细胞甲基化的结果直接导致了男性对5ARI治疗缺乏敏感性， 前列腺增生。为了证明SRD 5A 2表观遗传学变化的临床意义，并证实其在 调节对5ARI治疗的敏感性，我们提出以下目标：具体目标1：评估 5-AR 2表达在对5-ARI疗法的抗性的发展中。具体目标2：证明 SRD 5A 2甲基化开启雌激素途径，影响BPH男性对5ARI疗法的敏感性。 具体目的3：确定前列腺炎症与SRD 5A 2启动子甲基化的关系。 我们的研究结果对开发预测性生物标志物检测具有广泛的意义， 评估对BPH相关疗法的耐药性，并允许临床医生选择替代疗法来管理 最常见的增殖性疾病影响全世界的男性。

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.