Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6.
Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6.
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DOI：
10.1158/0008-5472.can-16-0455
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发表时间：
2017-02-01
期刊：
影响因子：
11.2
通讯作者：
Hahn WC
中科院分区：
文献类型：
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作者：
Choudhury AD;Schinzel AC;Cotter MB;Lis RT;Labella K;Lock YJ;Izzo F;Guney I;Bowden M;Li YY;Patel J;Hartman E;Carr SA;Schenone M;Jaffe JD;Kantoff PW;Hammerman PS;Hahn WC
在前列腺癌中，去势抵抗的发展是发展为侵袭性疾病的关键。然而，对所涉及的途径的理解仍然不完整。在这项研究中，我们进行了高通量遗传筛选，以确定雄激素依赖性前列腺上皮（LHSR-AR）细胞在雄激素缺乏的条件下能够形成肿瘤的激酶。除了鉴定已知的去势抗性介质（这有助于验证筛选）外，我们还鉴定了一种与有丝分裂相关的丝氨酸/苏氨酸激酶NEK6，作为雄激素非依赖性肿瘤生长的介质。NEK6在人类前列腺癌的一个亚群中过表达。在小鼠异种移植模型系统中，沉默抗去势癌细胞中的NEK6足以恢复对去势的敏感性。NEK6赋予去势抗性的肿瘤在组织学上主要是鳞状的，没有AR信号的证据。基因表达谱显示NEK6过表达刺激细胞骨架、分化和免疫信号通路，维持阉割后正常的基因表达模式。磷酸化蛋白质组分析显示转录因子FOXJ2是一种新的NEK6底物，FOXJ2的磷酸化与新发现的NEK6转录靶点的表达增加有关。总之，我们的研究确定NEK6信号是介导去势抵抗性前列腺癌的中心机制。
In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we identified a mitotic-related serine/threonine kinase, NEK6, as a mediator of androgen-independent tumor growth. NEK6 was overexpressed in a subset of human prostate cancers. Silencing NEK6 in castration-resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Tumors in which castration resistance was conferred by NEK6 were predominantly squamous in histology with no evidence of AR signaling. Gene expression profiling suggested that NEK6 overexpression stimulated cytoskeletal, differentiation and immune signaling pathways and maintained gene expression patterns normal decreased by castration. Phosphoproteome profiling revealed the transcription factor FOXJ2 as a novel NEK6 substrate, with FOXJ2 phosphorylation associated with increased expression of newly identified NEK6 transcriptional targets. Overall, our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer.