The androgen receptor couples promoter recruitment of RNA processing factors to regulation of alternative polyadenylation at the 3' end of transcripts.
The androgen receptor couples promoter recruitment of RNA processing factors to regulation of alternative polyadenylation at the 3' end of transcripts.
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在转录本的3'末端调节RNA加工因子的雄激素受体伴侣启动子募集。
DOI：
10.1093/nar/gkac737
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发表时间：
2022-09-23
影响因子：
14.9
通讯作者：
Sette, Claudio
中科院分区：
文献类型：
--
作者：
Caggiano, Cinzia;Pieraccioli, Marco;Pitolli, Consuelo;Babini, Gabriele;Zheng, Dinghai;Tian, Bin;Bielli, Pamela;Sette, Claudio
前列腺癌（PC）依赖于雄激素受体（AR）信号传导。虽然激素治疗（HT）是有效的，但大多数患者会发展到无法治愈的去势抵抗期（CRPC）。迄今为止，大多数提出的获得性耐药性HT的机制集中在AR转录活性。在这里，我们发现了一个新的作用，AR在交替切割和聚腺苷酸化（阿帕）。Enzalutamide对AR的抑制可全面调节PC细胞中的阿帕，与转录和DNA拓扑结构相关的基因特异性富集，表明其参与转录组重编程。AR抑制选择启动子远端多聚腺苷酸化位点（PA）富含由切割和多聚腺苷酸化特异性因子（CPSF）复合物识别的顺式元件。相反，启动子近端内含子PA依赖于切割刺激因子（CSTF）复合物被抑制。从机制上讲，Enzalutamide诱导阿帕亚复合物重排，并损害CPSF和CSTF之间的相互作用。AR抑制还诱导共转录CPSF募集到基因启动子，使依赖于该复合物的PA的选择倾向。重要的是，支架CPSF 160蛋白在CRPC细胞中上调，其耗尽抑制HT诱导的阿帕模式。这些发现揭示了AR在阿帕调节中的意想不到的作用，并表明APA介导的转录组重编程代表了PC细胞对HT的适应性反应。
Prostate cancer (PC) relies on androgen receptor (AR) signaling. While hormonal therapy (HT) is efficacious, most patients evolve to an incurable castration-resistant stage (CRPC). To date, most proposed mechanisms of acquired resistance to HT have focused on AR transcriptional activity. Herein, we uncover a new role for the AR in alternative cleavage and polyadenylation (APA). Inhibition of the AR by Enzalutamide globally regulates APA in PC cells, with specific enrichment in genes related to transcription and DNA topology, suggesting their involvement in transcriptome reprogramming. AR inhibition selects promoter-distal polyadenylation sites (pAs) enriched in cis-elements recognized by the cleavage and polyadenylation specificity factor (CPSF) complex. Conversely, promoter-proximal intronic pAs relying on the cleavage stimulation factor (CSTF) complex are repressed. Mechanistically, Enzalutamide induces rearrangement of APA subcomplexes and impairs the interaction between CPSF and CSTF. AR inhibition also induces co-transcriptional CPSF recruitment to gene promoters, predisposing the selection of pAs depending on this complex. Importantly, the scaffold CPSF160 protein is up-regulated in CRPC cells and its depletion represses HT-induced APA patterns. These findings uncover an unexpected role for the AR in APA regulation and suggest that APA-mediated transcriptome reprogramming represents an adaptive response of PC cells to HT.
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影响因子：
10.5
作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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