CBX8 Exhibits Oncogenic Activity via AKT/β-Catenin Activation in Hepatocellular Carcinoma
CBX8 Exhibits Oncogenic Activity via AKT/β-Catenin Activation in Hepatocellular Carcinoma
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DOI：
10.1158/0008-5472.can-17-0700
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发表时间：
2018-01-01
期刊：
影响因子：
11.2
通讯作者：
Yun, Jing-Ping
中科院分区：
文献类型：
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作者：
Zhang, Chris Zhiyi;Chen, Shi-Lu;Yun, Jing-Ping
多梳蛋白的失调影响肝细胞癌的发生和进展。本研究显示，在两个独立的共879例的队列中，色盒8 （CBX8）表达在肝细胞癌中增加，并与预后不良相关。CBX8的异位表达促进了肿瘤的生长和转移，而CBX8的沉默抑制了这些作用。CBX8通过上调转录因子EGR1和miR-365-3p以非规范方式有效激活AKT/ β -连环蛋白信号通路：CBX8直接结合EGR1启动子以增强其活性。在细胞核中，CBX8也与EGR1相互作用以防止其降解。此外，CBX8增加了miR-365a-3p的转录，通过靶向3'-UTR ZNRF1促进了β -catenin的核定位。抑制EGR1或miR-365a-3p部分挽救cbx8介导的恶性表型。在临床样本中，CBX8的表达与EGR1、miR-365a-3p和核β -连环蛋白密切相关。综上所述，我们的研究结果表明CBX8作为癌基因上调EGR1和miR-365-3p，从而刺激AKT/ β -catenin通路。这个新发现的信号轴可能为治疗肝细胞癌提供新的策略。(c) 2017 aacr。
Deregulation of polycomb proteins influences the development and progression of hepatocellular carcinoma. Here we show that chromobox 8 (CBX8) expression is increased in hepatocellular carcinoma and correlates with poor outcome in two independent cohorts containing a total of 879 cases. Ectopic expression of CBX8 facilitated tumor growth and metastasis, whereas CBX8 silencing suppressed these effects. CBX8 efficiently activated AKT/beta-catenin signaling via upregulation of the transcription factor EGR1 and miR-365-3p in a noncanonical manner: CBX8 directly bound the EGR1 promoter to enhance its activity. In the nucleus, CBX8 also interacted with EGR1 to prevent its degradation. Furthermore, CBX8 increased the transcription of miR-365a-3p, which promoted the nuclear localization of beta-catenin by targeting the 3'-UTR ZNRF1. Inhibiting either EGR1 or miR-365a-3p partially rescued CBX8-mediated malignant phenotypes. In clinical samples, CBX8 expression closely correlated with EGR1, miR-365a-3p, and nuclear beta-catenin. Collectively, our results show that CBX8 functions as an oncogene to upregulate EGR1 and miR-365-3p to stimulate the AKT/beta-catenin pathway. This newly identified signaling axis may suggest new therapeutic strategies against hepatocellular carcinoma. (C) 2017 AACR.