Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression.
Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression.
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DOI：
10.1158/1078-0432.ccr-15-1983
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发表时间：
2016-08-01
期刊：
影响因子：
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通讯作者：
Agoulnik IU
中科院分区：
文献类型：
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作者：
Lopez SM;Agoulnik AI;Zhang M;Peterson LE;Suarez E;Gandarillas GA;Frolov A;Li R;Rajapakshe K;Coarfa C;Ittmann MM;Weigel NL;Agoulnik IU
晚期前列腺癌的去势治疗最终失败，并导致去势抵抗性前列腺癌（CRPC）的发展，无法治愈。CRPC的特征性特征可以是雄激素受体（AR）表达增加和转录输出改变。我们研究了核受体辅阻遏物1（NCOR 1）在人前列腺和前列腺癌中的表达以及NCOR 1在抗雄激素反应中的作用。在409例患者样本中比较了匹配的正常前列腺和前列腺癌之间的NCOR 1蛋白水平。NCOR 1敲低用于研究其对雄激素依赖性前列腺癌细胞系中比卡鲁胺反应的影响以及与NCOR 1缺失相关的转录变化。还在前列腺癌基因表达数据集中检查了NCOR 1转录特征。正常前列腺组织中NCOR 1蛋白主要分布于前列腺分泌上皮细胞的胞浆和胞核。前列腺癌细胞质和细胞核NCOR 1蛋白水平均低于正常前列腺。前列腺癌转移显示NCOR 1转录输出显著降低。比卡鲁胺对LNCaP细胞增殖的抑制需要NCOR 1。NCOR 1调节基因抑制细胞增殖并介导比卡鲁胺耐药。在小鼠中，NCOR 1是AR靶基因亚组的比卡鲁胺依赖性调节所必需的。总之，我们证明了NCOR 1功能随着前列腺癌的进展而下降。NCOR 1水平的降低导致LNCaP细胞中的比卡鲁胺抗性，并在体内损害小鼠前列腺中对比卡鲁胺的应答。
Castration therapy in advanced prostate cancer eventually fails and leads to development of castration resistant prostate cancer (CRPC) which has no cure. Characteristic features of CRPC can be increased androgen receptor (AR) expression and altered transcriptional output. We investigated expression of Nuclear Receptor Corepressor 1 (NCOR1) in human prostate and prostate cancer and the role of NCOR1 in response to antiandrogens. NCOR1 protein levels were compared between matched normal prostate and prostate cancer in 409 patient samples. NCOR1 knockdown was used to investigate its effect on bicalutamide response in androgen-dependent prostate cancer cell lines and transcriptional changes associated with loss of NCOR1. NCOR1 transcriptional signature was also examined in prostate cancer gene expression datasets. NCOR1 protein was detected in cytoplasm and nuclei of secretory epithelial cells in normal prostate. Both cytoplasmic and nuclear NCOR1 protein levels were lower in prostate cancer than in normal prostate. Prostate cancer metastases show significant decrease in NCOR1 transcriptional output. Inhibition of LNCaP cellular proliferation by bicalutamide requires NCOR1. NCOR1 regulated genes suppress cellular proliferation and mediate bicalutamide resistance. In mouse, NCOR1 is required for bicalutamide dependent regulation of a subset of the AR target genes. In summary, we demonstrated that NCOR1 function declines with prostate cancer progression. Reduction in NCOR1 levels causes bicalutamide resistance in LNCaP cells and compromises response to bicalutamide in mouse prostate in vivo.