PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation

Tao Chen, Jingjie Li, Meidong Xu, Qin Zhao, Yingyong Hou, Liqing Yao, Yunshi Zhong, Ping-Chieh Chou, Wei Zhang (), Pinghong Zhou () and Yuhui Jiang ()
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Tao Chen: Fudan University
Jingjie Li: Shanghai Jiaotong University
Meidong Xu: Fudan University
Qin Zhao: Shanghai Jiaotong University
Yingyong Hou: Zhongshan Hospital, Fudan University
Liqing Yao: Fudan University
Yunshi Zhong: Fudan University
Ping-Chieh Chou: Comprehensive Cancer Center of Wake Forest Baptist Medical Center
Wei Zhang: Comprehensive Cancer Center of Wake Forest Baptist Medical Center
Pinghong Zhou: Fudan University
Yuhui Jiang: Shanghai Jiaotong University

Nature Communications, 2017, vol. 8, issue 1, 1-11

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.

Date: 2017
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DOI: 10.1038/s41467-017-01024-2

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