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SMAD2 Inactivation Inhibits CLDN6 Methylation to Suppress Migration and Invasion of Breast Cancer Cells

The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
Clinical Pathology Research Center, Department of Pathobiology, Qiqihar Medical University, Qiqihaer 161006, China
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2017, 18(9), 1863;
Received: 23 May 2017 / Revised: 22 August 2017 / Accepted: 22 August 2017 / Published: 30 August 2017
(This article belongs to the Special Issue Chemical and Molecular Approach to Tumor Metastases)
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The downregulation of tight junction protein CLDN6 promotes breast cancer cell migration and invasion; however, the exact mechanism underlying CLDN6 downregulation remains unclear. CLDN6 silence is associated with DNA methyltransferase 1 (DNMT1) mediated DNA methylation, and DNMT1 is regulated by the transforming growth factor beta (TGFβ)/SMAD pathway. Therefore, we hypothesized that TGFβ/SMAD pathway, specifically SMAD2, may play a critical role for CLDN6 downregulation through DNA methyltransferase 1 (DNMT1) mediated DNA methylation. To test this hypothesis, we blocked the SMAD2 pathway with SB431542 in two human breast cancer cell lines (MCF-7 and SKBR-3). Our results showed that treatment with SB431542 led to a decrease of DNMT1 expression and the binding activity for CLDN6 promoter. The methylation level of CLDN6 promoter was decreased, and simultaneously CLDN6 protein expression increased. Upregulation of CLDN6 inhibited epithelial to mesenchymal transition (EMT) and reduced the migration and invasion ability of both MCF-7 and SKBR-3 cells. Furthermore, knocked down of CLDN6 abolished SB431542 effects on suppression of EMT associated gene expression and inhibition of migration and invasion. Thus, we demonstrated that the downregulation of CLDN6 is regulated through promoter methylation by DNMT1, which depends on the SMAD2 pathway, and that CLDN6 is a key regulator in the SMAD2/DNMT1/CLDN6 pathway to inhibit EMT, migration and invasion of breast cancer cells. View Full-Text
Keywords: CLDN6; DNMT1; methylation; SMAD2; breast cancer CLDN6; DNMT1; methylation; SMAD2; breast cancer

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Lu, Y.; Wang, L.; Li, H.; Li, Y.; Ruan, Y.; Lin, D.; Yang, M.; Jin, X.; Guo, Y.; Zhang, X.; Quan, C. SMAD2 Inactivation Inhibits CLDN6 Methylation to Suppress Migration and Invasion of Breast Cancer Cells. Int. J. Mol. Sci. 2017, 18, 1863.

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