Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer.
Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer.
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DOI：
10.1016/j.celrep.2016.03.038
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发表时间：
2016-04-19
期刊：
影响因子：
8.8
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Zhao Y;Wang L;Ren S;Wang L;Blackburn PR;McNulty MS;Gao X;Qiao M;Vessella RL;Kohli M;Zhang J;Karnes RJ;Tindall DJ;Kim Y;MacLeod R;Ekker SC;Kang T;Sun Y;Huang H
雄激素受体 (AR) 是去势抵抗性前列腺癌 (CRPC) 进展所必需的，但 AR 结合增强子的功能和疾病相关性仍不清楚。在这里，我们鉴定了一组 AR 调节的增强子 RNA（例如 PSA eRNA），它们在 CRPC 细胞、患者来源的异种移植物（PDX）和患者组织中表达上调。 PSA eRNA 与 CYCLIN T1 结合，激活 P-TEFb，并通过增加 RNA 聚合酶 II (Pol II-Ser2p) 的丝氨酸 2 磷酸化来促进顺式和反式靶基因转录。我们在 PSA eRNA 中定义了 CYCLIN T1 结合所需的 HIV-1 TAR RNA 样 (TAR-L) 基序。使用 TALEN 介导的基因编辑，我们进一步证明该基序对于增加 Pol II-Ser2p 占用水平和 CRPC 细胞生长至关重要。我们发现了 P-TEFb 激活机制，并揭示了与异常 AR 功能相关的 eRNA 表达改变，可能是 CRPC 的潜在治疗靶点。赵等人。显示一组 AR 调节的 eRNA（包括 PSA eRNA）在培养的 CRPC 细胞以及患者样本中上调。 PSA eRNA 与 CYCLIN T1 结合，激活 P-TEFb 并增加 Pol II-Ser2p 和细胞生长，这种作用是通过 TAR-L 基序介导的。
The androgen receptor (AR) is required for castration resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g. PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDX) and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC. Zhao et al. show that a group of AR-regulated eRNAs, including the PSA eRNA are upregulated in CRPC cells in culture as well as in patient specimens. The PSA eRNA binds to CYCLIN T1, activates P-TEFb and increases Pol II-Ser2p and cell growth, and this effect is mediated through a TAR-L motif.