Modeling truncated AR expression in a natural androgen responsive environment and identification of RHOB as a direct transcriptional target.
Modeling truncated AR expression in a natural androgen responsive environment and identification of RHOB as a direct transcriptional target.
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DOI：
10.1371/journal.pone.0049887
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kung HJ
中科院分区：
文献类型：
--
作者：
Tsai HC;Boucher DL;Martinez A;Tepper CG;Kung HJ
最近的研究发现，具有配体非依赖性活性的雄激素受体亚型可能被截断，这为前列腺癌雄激素耗竭非依赖性生长的获得提供了新的线索。在这项研究中，我们提出了一个模型系统，在该模型中，雄激素受体的C末端截短变体(TC-AR)在雄激素依赖细胞系LNCaP中诱导表达，该细胞株表达少量截断的受体。我们观察到，当TC-AR过度表达时，内源性全长受体(FL-AR)转录下调。这在本质上允许我们用TC-AR“取代”FL-AR，并在完全相同的遗传和细胞背景下比较它们的个体属性，这是以前从未进行过的。我们发现，TC-AR移位到细胞核，在没有DHT的情况下激活AR靶基因的转录，并足以使ADI生长到正常雄激素依赖的LNCaP系。我们还表明，虽然FL-AR和TC-AR调控的基因有显着重叠，但目标基因的各自套组也存在差异，两种AR形成另一种不同的调控基因。在TC-AR唯一激活的基因中有RHOB，它被证明与LN/TC-AR中观察到的增加迁移和形态变化有关，提示RHOB在调节前列腺癌细胞雄激素非依赖性行为中发挥作用。
Recent studies identifying putative truncated androgen receptor isoforms with ligand-independent activity have shed new light on the acquisition of androgen depletion independent (ADI) growth of prostate cancer. In this study, we present a model system in which a C-terminally truncated variant of androgen receptor (TC-AR) is inducibly expressed in LNCaP, an androgen-dependent cell line, which expresses little truncated receptor. We observed that when TC-AR is overexpressed, the endogenous full length receptor (FL-AR) is transcriptionally downmodulated. This in essence allows us to “replace” FL-AR with TC-AR and compare their individual properties in exactly the same genetic and cellular background, which has not been performed before. We show that the TC-AR translocates to the nucleus, activates transcription of AR target genes in the absence of DHT and is sufficient to confer ADI growth to the normally androgen dependent LNCaP line. We also show that while there is significant overlap in the genes regulated by FL- and TC-AR there are also differences in the respective suites of target genes with each AR form regulating genes that the other does not. Among the genes uniquely activated by TC-AR is RHOB which is shown to be involved in the increased migration and morphological changes observed in LN/TC-AR, suggesting a role of RHOB in the regulation of androgen-independent behavior of prostate cancer cells.