The clinical success of combined androgen deprivation therapy (ADT) and radiation therapy (RT) in prostate cancer (PCa) created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes in nascent RNA transcription in response to IR, the AR antagonist enzalutamide, or the combination of the two, we find that enzalutamide treatment significantly decreased expression of canonical AR target genes but had no effect on DDR gene sets in PCa cells. Surprisingly, we also found that the AR is not a primary regulator of DDR genes either in response to IR or at steady state in asynchronously growing PCa cells. Implications: Our data indicate that the clinical benefit of combining ADT with RT is not due to direct AR regulation of DDR gene transcription, and that the field needs to consider alternative mechanisms for this clinical benefit.

中文翻译：

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雄激素受体不直接调节DNA损伤反应基因的转录。

雄激素剥夺疗法 (ADT) 和放射疗法 (RT) 联合治疗前列腺癌 (PCa) 的临床成功引起了人们对了解雄激素受体 (AR) 信号传导与 DNA 损伤反应 (DDR) 之间机制联系的兴趣。融合数据形成了一种模型，其中 AR 既监管 DDR，又受 DDR 监管。该模型的一个重要组成部分是 AR 在稳态和电离辐射 (IR) 响应下调节 DDR 基因的转录。在这项研究中，我们试图确定 IR 以 AR 依赖性方式诱导哪些直接转录变化。使用 PRO-seq 量化新生 RNA 转录响应 IR、AR 拮抗剂恩杂鲁胺或两者组合的变化，我们发现恩杂鲁胺治疗显着降低了典型 AR 靶基因的表达，但对 DDR 基因组没有影响前列腺癌细胞。令人惊讶的是，我们还发现，在异步生长的 PCa 细胞中，无论是响应 IR 还是处于稳定状态，AR 都不是 DDR 基因的主要调节因子。启示：我们的数据表明，ADT 与 RT 相结合的临床益处并不是由于 DDR 基因转录的直接 AR 调节，并且该领域需要考虑这种临床益处的替代机制。