Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer.
Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer.
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Neuropilin-2调节晚期前列腺癌雄激素受体转录活性。
DOI：
10.1038/s41388-022-02382-y
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发表时间：
2022-07
期刊：
影响因子：
8
通讯作者：
Datta, Kaustubh
中科院分区：
文献类型：
--
作者：
Dutta, Samikshan;Polavaram, Navatha Shree;Islam, Ridwan;Bhattacharya, Sreyashi;Bodas, Sanika;Mayr, Thomas;Roy, Sohini;Albala, Sophie Alvarez Y.;Toma, Marieta, I;Darehshouri, Anza;Borkowetz, Angelika;Conrad, Stefanie;Fuessel, Susanne;Wirth, Manfred;Baretton, Gustavo B.;Hofbauer, Lorenz C.;Ghosh, Paramita;Pienta, Kenneth J.;Klinkebiel, David L.;Batra, Surinder K.;Muders, Michael H.;Datta, Kaustubh
雄激素受体（AR）转录活性异常是去势抵抗性前列腺癌（CRPC）发生的主要机制之一。因此，分析与CRPC相关的AR-转录复合物对于理解治疗抗性的机制是重要的。在研究其机制时，我们观察到一种称为神经纤毛蛋白-2（NRP 2）的跨膜蛋白在形成一种新的含有核孔蛋白的AR-转录复合物中起着贡献作用。使用免疫金电子显微镜，高分辨率共聚焦显微镜，染色质免疫沉淀，蛋白质组学，和其他生化技术，我们描绘了NRP 2的一个特定的剪接变体如何成为sumoylated配体刺激后，易位到内核膜的分子机制。NRP 2的这种剪接变体然后稳定AR和核孔蛋白之间的复合物，以促进CRPC特异性基因表达。在这种特定的转录复合物中，已经鉴定出AR的全长和剪接变体。基于体外细胞系的测定表明，NRP 2的缺失不仅使AR-核孔蛋白相互作用不稳定，而且抑制AR的转录活性。使用体内骨转移模型，我们发现NRP 2的抑制导致CRPC细胞对已建立的抗AR治疗（如enzalutamide）敏感。总之，我们的发现强调了NRP 2和AR的组合抑制作为治疗难治性前列腺癌的有效治疗策略的重要性。
Aberrant transcriptional activity of androgen receptor (AR) is one of the dominant mechanisms for developing of castration-resistant prostate cancer (CRPC). Analyzing AR-transcriptional complex related to CRPC is therefore important towards understanding the mechanism of therapy-resistance. While studying its mechanism, we observed that a transmembrane protein called neuropilin-2 (NRP2) plays a contributory role in forming a novel AR-transcriptional complex containing nuclear pore proteins. Using immunogold electron microscopy, high-resolution confocal microscopy, chromatin immunoprecipitation, proteomics, and other biochemical techniques, we delineated the molecular mechanism of how a specific splice variant of NRP2 becomes sumoylated upon ligand stimulation and translocates to the inner nuclear membrane. This splice variant of NRP2 then stabilizes the complex between AR and nuclear pore proteins to promote CRPC specific gene expression. Both full-length and splice variants of AR have been identified in this specific transcriptional complex. In vitro cell line-based assays indicated that depletion of NRP2 not only destabilizes the AR-nuclear pore protein interaction but also inhibits the transcriptional activities of AR. Using an in vivo bone metastasis model, we showed that the inhibition of NRP2 led to the sensitization of CRPC cells toward established anti-AR therapies such as enzalutamide. Overall, our finding emphasize the importance of combinatorial inhibition of NRP2 and AR as an effective therapeutic strategy against treatment refractory prostate cancer.
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DOI：
10.1111/iju.13137
发表时间：
2016-08
期刊：
International journal of urology : official journal of the Japanese Urological Association
影响因子：
--
作者：
Imamura Y;Sadar MD
通讯作者：
Sadar MD
DOI：
10.1083/jcb.136.3.531
发表时间：
1997-02-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fricker M;Hollinshead M;White N;Vaux D
通讯作者：
Vaux D
影响因子：
7.8
作者：
Gomez-Cavazos, J. Sebastian;Hetzer, Martin W.
通讯作者：
Hetzer, Martin W.
影响因子：
4.6
作者：
Dutta S;Roy S;Polavaram NS;Baretton GB;Muders MH;Batra S;Datta K
通讯作者：
Datta K
影响因子：
4
作者：
Dieppois, Guennaelle;Stutz, Francoise
通讯作者：
Stutz, Francoise