The androgen receptor regulates a druggable translational regulon in advanced prostate cancer
The androgen receptor regulates a druggable translational regulon in advanced prostate cancer
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DOI：
10.1126/scitranslmed.aax9364
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发表时间：
2019-07-31
影响因子：
17.1
通讯作者：
Hsieh, Andrew C.
中科院分区：
文献类型：
--
作者：
Liu, Yuzhen;Horn, Jessie L.;Hsieh, Andrew C.
雄激素受体（AR）是细胞分化和前列腺癌发展的驱动因素。大量的工作已经将这些正常和异常的细胞过程与mRNA转录联系起来;然而，AR调节转录后基因调控的程度仍然未知。在这里，我们证明了AR使用翻译机制来塑造细胞蛋白质组。我们表明，AR是一个负调节蛋白质合成，并确定一个意想不到的AR和翻译起始过程中的体内关系。这通过翻译抑制剂4 EBP 1的直接转录控制介导。我们证明，降低AR丰度增加了eIF 4F翻译起始复合物的组装，这驱动了增强的肿瘤细胞增殖。此外，我们发现了一个网络的促增殖mRNA的特点是富含鸟嘌呤的顺式调节元件，特别是敏感的eIF 4F过度活跃。使用遗传学和药理学方法，我们证明了eIF 4F复合物的解离逆转了增殖程序，导致临床前模型中肿瘤生长减少和存活率提高。我们的研究结果揭示了一个可药用的联系，在功能上连接的mRNA转录和翻译启动的过程中出现一类致命的AR缺陷型前列腺癌。
The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.