RBBP6, a RING finger-domain E3 ubiquitin ligase, induces epithelial-mesenchymal transition and promotes metastasis of colorectal cancer
RBBP6, a RING finger-domain E3 ubiquitin ligase, induces epithelial-mesenchymal transition and promotes metastasis of colorectal cancer
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RBBP6，一种RING指结构域E3泛素连接酶，诱导上皮间质转化并促进结直肠癌转移
DOI：
10.1038/s41419-019-2070-7
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发表时间：
2019
影响因子：
9
通讯作者：
Xiaoliang Wang
中科院分区：
文献类型：
--
作者：
Chao Xiao;Zhijie Zhou;Gang Wu;Xin Zhang;YuPeng Wang;Guohe Song;Erxun Ding;Xing Sun;Lin Zhong;Shanbao Li;Junyong Weng;Zhonglin Zhu;Jian Chen;Xiaoliang Wang
RBBP 6与肿瘤发生有关，但其在肿瘤转移和进展中的作用尚未评估。有趣的是，在这里，我们发现RBBP 6在结直肠癌（CRC）中上调，其表达水平与远处转移呈正相关。在这项研究中，我们鉴定了RBBP 6，一种RING Finger-domain E3泛素连接酶，作为一个独立的预后因素，并预测CRC患者的预后不良。RBBP 6在CRC细胞中促进细胞增殖、迁移和侵袭，并在小鼠模型中促进肿瘤生长、肺转移和肝转移。从机制上讲，我们发现RBBP 6结合并泛素化IκBα，一种NF-κ B信号通路的抑制剂。RBBP 6介导的IκBα泛素化和降解可显著促进p65核转位，进而激活NF-κB通路，诱导上皮-间充质转化（EMT）过程和细胞转移。此外，通过DNA甲基化结果和ChIP分析，我们证明RBBP 6的启动子是低甲基化的，并被多致癌转录因子激活。总之，我们的研究结果表明，RBBP 6可能是一个潜在的预后生物标志物和CRC侵袭和转移的治疗靶点。
RBBP6 has been implicated in tumorigenesis but its role in tumor metastasis and progression has not been evaluated. Interestingly, here we show that RBBP6 is upregulated in colorectal cancer (CRC) where its expression level is positively correlated with distant metastasis. In this study, we identified RBBP6, a RING Finger-domain E3 ubiquitin ligase, served as an independent prognostic factor and predicted poor outcome for CRC patients. RBBP6 promoted cell proliferation, migration, and invasion in CRC cells and promoted tumor growth, lung metastasis, and liver metastasis in mouse models. Mechanistically, we revealed that RBBP6 bound and ubiquitylated IκBα, an inhibitor of the NF-κB-signaling pathway. RBBP6-mediated ubiquitination and degradation of IκBα significantly enhanced p65 nuclear translocation, which triggered the activation of NF-κB pathway and then induced the epithelial–mesenchymal transition (EMT) process and cell metastasis. Furthermore, by DNA methylation results and ChIP analysis, we demonstrated that the promoter of RBBP6 was hypomethylated, and was activated by multi-oncogenic transcription factors. In conclusion, our findings suggest that RBBP6 may be a potential prognostic biomarker and therapeutic target for CRC invasion and metastasis.