Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation
Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation
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DOI：
10.1073/pnas.1324151111
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发表时间：
2014-05-20
影响因子：
11.1
通讯作者：
Kantoff, Philip W.
中科院分区：
文献类型：
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作者：
Hsieh, Chen-Lin;Fei, Teng;Kantoff, Philip W.
雄激素受体(AR)是调节前列腺癌细胞行为和命运的关键因素。当AR结合增强子元件并调节特定的增强子-启动子环时，AR调节的网络被激活。激肽释放酶相关多肽酶3(KLK3)编码前列腺特异性抗原(PSA)，是一个已知的AR调节基因，其上游增强子产生双向增强子RNA(ERNAs)，称为KLK3e。在这里，我们证明了KLK3e促进了KLK3增强子和KLK2启动子之间的空间相互作用，并增强了KLK2的远距离转录激活。KLK3e携带源于雄激素反应元件III(ARE III)的核心增强子元件，这是AR和介体1(MED1)相互作用所必需的。此外，我们发现KLK3e处理依赖于RNA的增强子活性依赖于核心增强子元件的完整性。在人前列腺组织中检测到KLK3e的转录，其表达与KLK3(R-2=0.6213，P<；5×10(-11))和KLK2(R-2=0.5893，P<；5×10(-10))显著相关。有趣的是，KLK3e的RNAi沉默对前列腺癌细胞的增殖有轻微的负面影响。因此，我们报道了雄激素诱导的Erna支架调节染色体结构并选择性地增强AR依赖的基因表达的AR相关蛋白复合体。
The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer-promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a well-known AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 (R-2 = 0.6213, P < 5 x 10(-11)) and KLK2 (R-2 = 0.5893, P < 5 x 10(-10)) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression.