Audet-Walsh Étienne, Yee Tracey, Tam Ingrid S, Giguère Vincent
Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Endocrinology. 2017 Apr 1;158(4):1015-1021. doi: 10.1210/en.2016-1926.
5α-Reductase types 1 and 2, encoded by SRD5A1 and SRD5A2, are the two enzymes that can catalyze the conversion of testosterone to dihydrotestosterone, the most potent androgen receptor (AR) agonist in prostate cells. 5α-Reductase type 2 is the predominant isoform expressed in the normal prostate. However, its expression decreases during prostate cancer (PCa) progression, whereas SRD5A1 increases, and the mechanism underlying this transcriptional regulatory switch is still unknown. Interrogation of SRD5A messenger RNA expression in three publicly available data sets confirmed that SRD5A1 is increased in primary and metastatic PCa compared with nontumoral prostate tissues, whereas SRD5A2 is decreased. Activation of AR, a major oncogenic driver of PCa, induced the expression of SRD5A1 from twofold to fourfold in three androgen-responsive PCa cell lines. In contrast, AR repressed SRD5A2 expression in this context. Chromatin-immunoprecipitation studies established that AR is recruited to both SRD5A1 and SRD5A2 genes following androgen stimulation but initiates transcriptional activation only at SRD5A1 as monitored by recruitment of RNA polymerase II and the presence of the H3K27Ac histone mark. Furthermore, we showed that the antiandrogens bicalutamide and enzalutamide block the AR-mediated regulation of both SRD5A1 and SRD5A2, highlighting an additional mechanism explaining their beneficial effects in patients. In summary, we identified an AR-dependent transcriptional regulation that explains the differential expression of 5α-reductase types 1 and 2 during PCa progression. Our work thus defines a mechanism by which androgens control their own synthesis via differential regulatory control of the expression of SRD5A1 and SRD5A2.
由SRD5A1和SRD5A2编码的1型和2型5α-还原酶是两种可催化睾酮转化为双氢睾酮的酶，双氢睾酮是前列腺细胞中最有效的雄激素受体（AR）激动剂。2型5α-还原酶是正常前列腺中表达的主要亚型。然而，在前列腺癌（PCa）进展过程中其表达降低，而SRD5A1表达增加，这种转录调控开关的潜在机制仍然未知。对三个公开数据集的SRD5A信使核糖核酸表达进行分析证实，与非肿瘤前列腺组织相比，原发性和转移性PCa中SRD5A1增加，而SRD5A2减少。AR作为PCa的主要致癌驱动因子，其激活在三种雄激素反应性PCa细胞系中使SRD5A1的表达增加了两倍至四倍。相比之下，在这种情况下AR抑制SRD5A2的表达。染色质免疫沉淀研究表明，雄激素刺激后AR被招募到SRD5A1和SRD5A2基因上，但如通过RNA聚合酶II的招募和H3K27Ac组蛋白标记的存在所监测的，仅在SRD5A1处启动转录激活。此外，我们表明抗雄激素药物比卡鲁胺和恩杂鲁胺可阻断AR介导的对SRD5A1和SRD5A2的调控，这突出了另一种解释它们对患者有益作用的机制。总之，我们确定了一种AR依赖性转录调控，解释了PCa进展过程中1型和2型5α-还原酶的差异表达。因此，我们的工作定义了一种机制，雄激素通过对SRD5A1和SRD5A2表达的差异调控来控制自身的合成。
