Expression, regulation and function of the ISGylation system in prostate cancer
Expression, regulation and function of the ISGylation system in prostate cancer
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DOI：
10.1038/onc.2009.115
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发表时间：
2009-07-16
期刊：
影响因子：
8
通讯作者：
Seliger, B.
中科院分区：
文献类型：
--
作者：
Kiessling, A.;Hogrefe, C.;Seliger, B.
雄激素受体（AR）在调节前列腺细胞增殖中起关键作用，并参与前列腺癌（PCa）的发生和进展。了解AR的复杂调节为PCa提供了新的治疗选择。在这里，我们表明：（i）泛素样修饰剂，干扰素刺激基因15（ISG 15），和大多数酶参与ISG 15共轭上调肿瘤样本中与非恶性组织的前列腺癌患者和（ii）这些组件的表达显着不同的患者之间的肿瘤雄激素消融治疗。使用PCa细胞系作为体外模型，证实了ISGylation组分的特异性雄激素介导的AR依赖性调节。此外，ISG化系统控制AR mRNA和蛋白表达，因为在AR（+）雄激素敏感性PCa细胞系LNCaP中，Ube 1 L作为限制性ISG化因子的过表达导致显著的AR上调，即使在雄激素剥夺下也伴随着增殖增加。因此，Ube 1 L敲低降低了AR表达。因此，本研究描述了。首次通过ISGylation组分调节AR表达，其影响PCa细胞的增殖，从而为ISGylation系统在恶性转化中的新功能提供证据。Oncogene（2009）28，2606-2620; doi：10.1038/onc.2009.115; 2009年5月11日在线发表
The androgen receptor (AR) plays a crucial role in the modulation of prostate cell proliferation and is involved in the development and progression of prostate cancer (PCa). An understanding of the complex regulation of AR provides novel treatment options for PCa. Here, we show (i) that the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), and most enzymes involved in ISG15 conjugation were upregulated in tumor samples versus in non-malignant tissues of PCa patients and (ii) that the expression of these components significantly differed between tumors in patients treated with and without androgen ablation. Using PCa cell lines as in vitro models, the specific androgen-mediated, AR-dependent regulation of the ISGylation components was confirmed. In addition, the ISGylation system controls AR mRNA and protein expressions, as overexpression of Ube1L as a limiting ISGylation factor in the AR(+) androgen-sensitive PCa cell line, LNCaP, results in significant AR upregulation, accompanied by an increased proliferation even under androgen deprivation. Accordingly, Ube1L knockdown decreased the AR expression. Thus, this study describes for the. first time the modulation of AR expression by ISGylation components, which affects the proliferation of PCa cells, thereby providing evidence for a novel function of the ISGylation system in malignant transformation. Oncogene (2009) 28, 2606-2620; doi: 10.1038/onc.2009.115; published online 11 May 2009