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Mol Cancer Res. 2019 Feb;17(2):655-665. doi: 10.1158/1541-7786.MCR-18-0637. Epub 2018 Nov 6.

Nuclear E-Cadherin Acetylation Promotes Colorectal Tumorigenesis via Enhancing β-Catenin Activity.

Author information

1
Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, P.R. China.
2
Department of Oncology, Jinan Central Hospital afflicted to Shandong University, Shandong, P.R. China.
3
Shanghai Key Laboratory of Mycobacterium Tuberculosis, Shanghai Pulmonary Hospital, Tongji University Medical School, Shanghai, P.R. China.
4
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Department of Periodontology, School of Stomatology, Tongji University, Shanghai, P.R. China.
5
Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, P.R. China. liufeng@sibs.ac.cn yueqin776@sina.com.

Abstract

The E-cadherin/β-catenin signaling pathway plays a critical role in the maintenance of epithelial architecture and regulation of tumor progression. Normally, E-cadherin locates on the cell surface with its cytosolic domain linking to the actin cytoskeleton through interaction with catenins. Although the nuclear localization of E-cadherin has been frequently observed in various types of cancers, little is known regarding the functional consequences of its nuclear translocation. Here, we showed that in colorectal cancer samples and cell lines, E-cadherin localized in the nucleus; and the nuclear localization was mediated through protein interaction with CTNND1. In the nucleus, E-cadherin was acetylated by CREB-binding protein at Lysine870 and Lysine871 in its β-catenin-binding domain, and the acetylation can be reversed by SIRT2. Acetylation of nuclear E-cadherin attenuated its interaction with β-catenin, which therefore released β-catenin from the complex, resulting in increased expression of its downstream genes and accelerated tumor growth and migration. Further study showed that acetylation level of nuclear E-cadherin had high prognostic significance in clinical colorectal samples. Taken together, our findings reveal a novel mechanism of tumor progression through posttranslational modification of E-cadherin, which may serve as a potential drug target of tumor therapy. IMPLICATIONS: This finding that acetylation of nuclear E-cadherin regulates β-catenin activity expands our understanding of the acetylation of E-cadherin promotes colorectal cancer cell growth and suggests novel therapeutic approaches of targeting acetylation in tumors.

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