Tip60 Promotes Prostate Cancer Cell Proliferation by Translocation of Androgen Receptor into the Nucleus
Tip60 Promotes Prostate Cancer Cell Proliferation by Translocation of Androgen Receptor into the Nucleus
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DOI：
10.1002/pros.21088
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发表时间：
2010-04-01
期刊：
影响因子：
2.8
通讯作者：
Naito, Seiji
中科院分区：
文献类型：
--
作者：
Shiota, Masaki;Yokomizo, Akira;Naito, Seiji
背景目前，去势抵抗性前列腺癌（CRPCa）的有效疗法很少。对去势抵抗的CRPC被认为是由雄激素/雄激素受体（AR）信号通路的激活增加引起的，这可能被AR辅激活剂增强。荧光素酶报告基因分析、Western印迹、实时定量聚合酶链反应、荧光显微镜、细胞增殖分析和流式细胞术细胞周期分析被用于解决Tip 60调节AR在PCa细胞中的作用。Tip 60独立调节AR靶基因雄激素的转录。Tip 60敲低诱导AR易位到细胞质中。核定位信号序列中的乙酰化模拟突变导致AR蛋白主要定位在细胞核中，尽管雄激素饥饿，而非乙酰化模拟突变导致AR主要定位在细胞质中，尽管雄激素刺激。Tip 60在去势抵抗LNCaP衍生CXR细胞中的过表达导致AR的乙酰化形式和AR在细胞核中的定位增加，即使没有雄激素。因此，Tip 60沉默通过诱导细胞周期停滞在G1期来抑制表达AR的PCa细胞的生长，类似于抑制雄激素/AR信号传导。此外，Tip 60基因敲低抑制了CxR细胞的生长。Tip 60作为AR共激活因子参与PCa细胞的增殖。Tip 60表达或功能的调节可能是一种有用的策略，用于开发新的治疗PCa，甚至CRPC，这仍然依赖于AR信号，通过过表达AR及其共激活剂。前列腺70：540-554，2010年。(C)2009威利-利斯公司
BACKGROUND. There are currently few effective therapies for castration-resistant prostate cancer (CRPCa). CRPC which is resistant to castration is thought to result from increased activation of the androgen/androgen receptor (AR) signaling pathway, which may be augmented by AR coactivators.METHODS. Luciferase reporter assay, Western blotting, quantitative real-time polymerase chain reaction, fluorescence microscopy, cell proliferation assay, and flow cytometry for cell-cycle analysis were used to resolve a role of Tip60 regulating AR in PCa cells.RESULTS. Tip60 regulated transcriptions of AR target genes androgen independently. Tip60 knockdown induced translocation of AR into the cytoplasm. Acetylation-mimicking mutations in the nuclear localization signal sequence caused AR protein to mainly localize in the nucleus despite androgen starvation, whereas non-acetylation-mimicking mutations caused AR to mainly localize in the cytoplasm despite androgen stimulation. Tip60 overexpression in castration-resistant LNCaP derivative CxR cells resulted in increases in the acetylated form of AR and AR localization in the nucleus even without androgen. Consequently, Tip60 silencing suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G1 phase, similar to inhibition of androgen/AR signaling. Furthermore, Tip60 knockdown suppressed the cell growth of CxR cells.CONCLUSIONS. Tip60 is involved in the proliferation of PCa cells as an AR coactivator. Modulation of Tip60 expression or function may be a useful strategy for developing novel therapeutics for PCa, even CRPC, which remain dependent on AR signaling, by overexpressing AR and its coactivators. Prostate 70: 540-554, 2010. (C) 2009 Wiley-Liss, Inc.