Androgen receptor signaling regulates DNA repair in prostate cancers.
Androgen receptor signaling regulates DNA repair in prostate cancers.
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雄激素受体信号调节前列腺癌的 DNA 修复。
DOI：
10.1158/2159-8290.cd-13-0172
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发表时间：
2013-11
期刊：
影响因子：
28.2
通讯作者：
Sawyers CL
中科院分区：
文献类型：
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作者：
Polkinghorn WR;Parker JS;Lee MX;Kass EM;Spratt DE;Iaquinta PJ;Arora VK;Yen WF;Cai L;Zheng D;Carver BS;Chen Y;Watson PA;Shah NP;Fujisawa S;Goglia AG;Gopalan A;Hieronymus H;Wongvipat J;Scardino PT;Zelefsky MJ;Jasin M;Chaudhuri J;Powell SN;Sawyers CL
我们证明，雄激素受体（AR）调节DNA修复基因的转录程序，促进前列腺癌的放射抗性，提供了一个潜在的机制，雄激素剥夺治疗（ADT）与电离辐射（IR）协同作用。使用去势抵抗性前列腺癌的模型，我们发现第二代抗雄激素治疗导致DNA修复基因下调。接下来，我们证明了原发性前列腺癌显示与一组DNA修复基因的表达相关的AR转录输出的显著谱。利用RNA-seq和ChIP-seq，我们确定了这些DNA修复基因中哪些是由雄激素诱导的，并代表了直接的AR靶标。我们确定，IR加雄激素治疗的前列腺癌细胞表现出增强的DNA修复和减少的DNA损伤，此外，抗雄激素治疗导致DNA损伤增加和克隆存活率降低。最后，我们证明，抗雄激素治疗的结果减少经典的非同源末端连接。
We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy (ADT) synergizes with ionizing radiation (IR). Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output which correlates with expression of a set of DNA repair genes. Employing RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with IR plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical non-homologous end joining.