Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2.
Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2.
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在castration-抗性前列腺癌中增加的AR表达迅速诱导AR信号传导与EZH2的协作重编程。
DOI：
10.3389/fonc.2022.1021845
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
雄激素受体（AR）表达升高是去势抵抗性前列腺癌（CRPC）的标志，有助于雄激素剥夺条件下AR信号的恢复。然而，是否过表达的AR单独与刺激去势水平的雄激素可以足以诱导AR信号的重编程，以适应前列腺癌（PCa）细胞仍然不清楚。在这项研究中，我们使用了一个PCa模型与诱导型AR过度表达，以检查急性影响AR过度表达的顺式组和转录组。我们的研究结果表明，AR单独过表达结合较低的雄激素水平可以迅速重新分配AR染色质结合，并激活一个独特的转录程序，这是丰富的DNA损伤修复途径。此外，使用最近开发的生物信息学工具，我们预测了EZH 2参与这种AR重编程，随后确定了AR/EZH 2共靶向基因的子集，这些基因在CRPC中过表达，并与更差的患者结局相关。从机制上讲，我们发现AR-EZH 2相互作用受到去势前雄激素水平的损害，但可以通过去势后雄激素水平恢复。总的来说，我们的研究为AR信号重编程与特定表观遗传因子的参与提供了新的分子见解。
Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
16.6
作者：
Lim Y;Arora S;Schuster SL;Corey L;Fitzgibbon M;Wladyka CL;Wu X;Coleman IM;Delrow JJ;Corey E;True LD;Nelson PS;Ha G;Hsieh AC
通讯作者：
Hsieh AC
影响因子：
16.6
作者：
Jin, Hong-Jian;Zhao, Jonathan C.;Wu, Longtao;Kim, Jung;Yu, Jindan
通讯作者：
Yu, Jindan
影响因子：
2
作者：
Cai C;Yuan X;Balk SP
通讯作者：
Balk SP
DOI：
10.1073/pnas.2105898119
发表时间：
2022-01-18
影响因子：
11.1
作者：
Liao Y;Chen CH;Xiao T;de la Peña Avalos B;Dray EV;Cai C;Gao S;Shah N;Zhang Z;Feit A;Xue P;Liu Z;Yang M;Lee JH;Xu H;Li W;Mei S;Pierre RS;Shu S;Fei T;Duarte M;Zhao J;Bradner JE;Polyak K;Kantoff PW;Long H;Balk SP;Liu XS;Brown M;Xu K
通讯作者：
Xu K