PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Chen, Tao; Li, Jingjie; Xu, Meidong; Zhao, Qin; Hou, Yingyong; Yao, Liqing; Zhong, Yunshi; Chou, Ping-Chieh; Zhang, Wei; Zhou, Pinghong; Jiang, Yuhui
• Is Part Of: Nature communications. Volume 8:Issue 1(2017)
• Page Start: 1
• Page End: 11
• Publication Date: 2017-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-017-01024-2
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract EGFR signaling is implicated in NF-κB activation. However, the concrete mechanisms by which the core transducer of NF-κB signaling pathway, RelA/p65 is regulated under EGFR activation remains to be further clarified. Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migration and invasion inhibitory protein (MIIP) at Ser303; this phosphorylation promotes the interaction between MIIP and RelA in the nucleus, by which MIIP prevents histone deacetylase 6 (HDAC6)-mediated RelA deacetylation, and thus enhances transcriptional activity of RelA and facilitates tumor metastasis. Meanwhile PP1, which functions as a phosphatase, is found to mediate MIIP-S303 dephosphorylation and its expression level inversely correlates with metastatic capability of tumor cells. Moreover, clinical analyses indicate the level of MIIP-S303 phosphorylation correlates with colorectal cancer (CRC) metastasis and prognosis. These findings uncover an unidentified mechanism underlying the precise regulation of NF-κB by EGF, and highlight the critical role of nuclear MIIP in tumor metastasis. In colorectal cancer, EGFR signalling is implicated in metastasis. Here, the authors unravel a mechanism through which EGF stimulation induces MIIP phosphorylation, leading to MIIP interacting with RelA—this prevents RelA deactylation and enhances transcriptional activity, facilitating metastasis.