Androgen receptor splice variants bind to constitutively open chromatin and promote abiraterone-resistant growth of prostate cancer.
Androgen receptor splice variants bind to constitutively open chromatin and promote abiraterone-resistant growth of prostate cancer.
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雄激素受体剪接变体与组成性开放染色质结合并促进前列腺癌的阿比特龙耐药生长
DOI：
10.1093/nar/gkx1306
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发表时间：
2018-02-28
影响因子：
14.9
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
He Y;Lu J;Ye Z;Hao S;Wang L;Kohli M;Tindall DJ;Li B;Zhu R;Wang L;Huang H
摘要雄激素受体（AR）剪接变异体（ARV）与去势抵抗性前列腺癌（CRPC）的发生有关。ARV的上调通常与雄激素剥夺治疗（ADT）后持续的AR活性相关。然而，ARV依赖性顺式组的基因组和表观基因组特征以及ARV介导的转录组的疾病相关性仍然难以捉摸。通过整合染色质免疫沉淀偶联测序（ChIP-seq）和RNA测序（RNA-seq）分析，我们在CRPC细胞中鉴定了ARV优先结合位点（ARV-PBS）和一组优先被ARV反式激活的基因。ARV优先结合位于含有完整AR反应元件（AREfull）的核小体耗尽区域中的增强子，而全长AR（ARFL）-PBS是位于含有复合FOXA 1-nnnn-AREhalf基序的封闭染色质区域中的增强子。ARV-PBS仅与患者去势抵抗（CR）肿瘤中的AR结合位点重叠，并且ARV优先激活的基因在阿比特龙抵抗患者标本中上调。ARV-PBS靶基因的表达，如癌基因RAP 2A和细胞周期基因E2 F7，与去势抵抗、生存不良和肿瘤进展显著相关。我们揭示了ARV-PBS独特的基因组和表观基因组特征，强调ARV是描述前列腺癌中AR调节的致癌基因组和表观基因组景观的有用工具。我们的数据还表明，ARV优先激活的转录程序可以靶向有效治疗CRPC。
Abstract Androgen receptor (AR) splice variants (ARVs) are implicated in development of castration-resistant prostate cancer (CRPC). Upregulation of ARVs often correlates with persistent AR activity after androgen deprivation therapy (ADT). However, the genomic and epigenomic characteristics of ARV-dependent cistrome and the disease relevance of ARV-mediated transcriptome remain elusive. Through integrated chromatin immunoprecipitation coupled sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, we identified ARV-preferential-binding sites (ARV-PBS) and a set of genes preferentially transactivated by ARVs in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions harboring the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions containing the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in castration-resistant (CR) tumors in patients and ARV-preferentially activated genes were up-regulated in abiraterone-resistant patient specimens. Expression of ARV-PBS target genes, such as oncogene RAP2A and cell cycle gene E2F7, were significantly associated with castration resistance, poor survival and tumor progression. We uncover distinct genomic and epigenomic features of ARV-PBS, highlighting that ARVs are useful tools to depict AR-regulated oncogenic genome and epigenome landscapes in prostate cancer. Our data also suggest that the ARV-preferentially activated transcriptional program could be targeted for effective treatment of CRPC.
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影响因子：
3.4
作者：
Bluemn EG;Nelson PS
通讯作者：
Nelson PS
影响因子：
30.8
作者：
He, Housheng Hansen;Meyer, Clifford A.;Shin, Hyunjin;Bailey, Shannon T.;Wei, Gang;Wang, Qianben;Zhang, Yong;Xu, Kexin;Ni, Min;Lupien, Mathieu;Mieczkowski, Piotr;Lieb, Jason D.;Zhao, Keji;Brown, Myles;Liu, X. Shirley
通讯作者：
Liu, X. Shirley
影响因子：
--
作者：
Jones D;Wade M;Nakjang S;Chaytor L;Grey J;Robson CN;Gaughan L
通讯作者：
Gaughan L
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：
3.9
作者：
Dehm SM;Tindall DJ
通讯作者：
Tindall DJ