Protein 4.1N acts as a potential tumor suppressor linking PP1 to JNK-c-Jun pathway regulation in NSCLC
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Zi Wang1,2,*, Bianyin Ma1,*, Hui Li1,*, Xiaojuan Xiao1,*, Weihua Zhou1,3, Feng Liu2, Bin Zhang4, Min Zhu1, Qin Yang1, Yayue Zeng1, Yang Sun5, Shuming Sun1, Yanpeng Wang1, Yibin Zhang1, Haibo Weng6, Lixiang Chen6, Mao Ye5, Xiuli An6,7, Jing Liu1
1The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China
2Department of Medicine, University of California, Irvine, CA, USA
3Department of Biochemistry, College of Medicine, Jishou University, Jishou, China
4Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
5Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, China
6College of Life Sciences, Zhengzhou University, Zhengzhou, China
7Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA
*These authors contributed equally to this work
Xiuli An, e-mail: [email protected]
Mao Ye, e-mail: [email protected]
Keywords: protein 4.1N, non-small cell lung cancer, tumor suppressor, PP1, JNK/c-Jun pathway
Received: October 29, 2015 Accepted: November 02, 2015 Published: November 13, 2015
Protein 4.1N is a member of protein 4.1 family and has been recognized as a potential tumor suppressor in solid tumors. Here, we aimed to investigate the role and mechanisms of 4.1N in non-small cell lung cancer (NSCLC). We confirmed that the expression level of 4.1N was inversely correlated with the metastatic properties of NSCLC cell lines and histological grade of clinical NSCLC tissues. Specific knockdown of 4.1N promoted tumor cell proliferation, migration and adhesion in vitro, and tumor growth and metastasis in mouse xenograft models. Furthermore, we identified PP1 as a novel 4.1N-interacting molecule, and the FERM domain of 4.1N mediated the interaction between 4.1N and PP1. Further, ectopic expression of 4.1N could inactivate JNK-c-Jun signaling pathway through enhancing PP1 activity and interaction between PP1 and p-JNK. Correspondingly, expression of potential downstream metastasis targets (ezrin and MMP9) and cell cycle targets (p53, p21 and p19) of JNK-c-Jun pathway were also regulated by 4.1N. Our data suggest that down-regulation of 4.1N expression is a critical step for NSCLC development and that repression of JNK-c-Jun signaling through PP1 is one of the key anti-tumor mechanisms of 4.1N.
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