Human heterochromatin protein 1 isoform HP1beta enhances androgen receptor activity and is implicated in prostate cancer growth.
Human heterochromatin protein 1 isoform HP1beta enhances androgen receptor activity and is implicated in prostate cancer growth.
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DOI：
10.1677/erc-09-0321
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发表时间：
2010-06
影响因子：
3.9
通讯作者：
M. Shiota;Y. Song;A. Yokomizo;Y. Tada;K. Kuroiwa;M. Eto;Y. Oda;J. Inokuchi;T. Uchiumi;N. Fujimoto;N. Seki;S. Naito
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文献类型：
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作者：
M. Shiota;Y. Song;A. Yokomizo;Y. Tada;K. Kuroiwa;M. Eto;Y. Oda;J. Inokuchi;T. Uchiumi;N. Fujimoto;N. Seki;S. Naito
目前，治疗去势抵抗性前列腺癌（CRPC）的成功方法很少。CRPC被认为是由雄激素/雄激素受体（AR）信号通路的增强激活引起的，AR辅助因子可以增强这一信号通路。在本研究中，发现异染色质蛋白1 β (hp1 β)是AR辅助因子，而不是hp1 α或hp1 γ。hp1 β与AR相互作用，增强AR与前列腺特异性抗原增强子和启动子区雄激素应答元件的dna结合能力，增加AR靶基因的转录。在前列腺癌（PCa）组织中，HP1beta的表达与Gleason评分和组蛋白H3赖氨酸9的三甲基化水平相关。沉默hp1 β通过诱导细胞周期阻滞在G(1)期来抑制AR表达的PCa细胞的生长，类似于抑制雄激素/AR信号传导。此外，HP1beta在抗去势LNCaP衍生的CxR细胞中过表达，HP1beta敲低也抑制了CxR细胞的生长。这些发现表明，hp1 β参与AR表达的PCa细胞的增殖和向CRPC的进展，作为AR共激活因子。调节hp1 β的表达或功能可能是开发新的PCa治疗方法的有用策略，即使在CRPC中也是如此。
There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, heterochromatin protein 1beta (HP1beta), but not HP1alpha or HP1gamma was found to be an AR cofactor. HP1beta interacted with the AR, and enhanced the DNA-binding ability of AR to androgen-responsive element in the prostate-specific antigen enhancer and promoter regions, and to increase the transcription of AR target genes. In prostate cancer (PCa) tissues, HP1beta expressions correlated with Gleason score and tri-methylation levels of histone H3 lysine 9. Silencing of HP1beta suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G(1) phase, similar to inhibition of androgen/AR signaling. Furthermore, HP1beta was overexpressed in castration-resistant LNCaP derivative CxR cells, and HP1beta knockdown also suppressed the cell growth in CxR cells. These findings indicate that HP1beta is involved in the proliferation of AR-expressing PCa cells and progression to CRPC as an AR coactivator. Modulation of HP1beta expression or function might be a useful strategy for developing novel therapeutics for PCa, even in CRPC.