DACT2 silencing by promoter CpG methylation disrupts its regulation of epithelial-to-mesenchymal transition and cytoskeleton reorganization in breast cancer cells
| Autor: | Chunhong Li, Yichao Fan, Guosheng Ren, Tingxiu Xiang, Yixiao Feng, Ying Ying, Weiyan Peng, Michael Oberst, Junhao Mu, Kathleen Kelly, Lili Li, Qian Tao |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology Carcinogenesis Fluorescent Antibody Technique Apoptosis medicine.disease_cause Molecular oncology Glycogen Synthase Kinase 3 0302 clinical medicine Genes Tumor Suppressor Cancer epigenetics Breast Enzyme Inhibitors skin and connective tissue diseases Promoter Regions Genetic Wnt Signaling Pathway Wnt signaling pathway EMT Flow Cytometry Neoplasm Proteins DNA Demethylation Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis DNA methylation Azacitidine Female Research Paper medicine.medical_specialty Epithelial-Mesenchymal Transition tumor suppressor Down-Regulation Breast Neoplasms Decitabine 03 medical and health sciences DACT2 Breast cancer breast cancer Cell Line Tumor medicine Humans Epigenetics Gene Silencing Adaptor Proteins Signal Transducing Cell Proliferation business.industry Cancer DNA Methylation medicine.disease 030104 developmental biology Cancer research CpG Islands methylation business Carrier Proteins Proto-Oncogene Proteins c-akt |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Tingxiu Xiang 1 , Yichao Fan 2 , Chunhong Li 3 , Lili Li 2 , Ying Ying 2 , Junhao Mu 1 , Weiyan Peng 1 , Yixiao Feng 1 , Michael Oberst 4 , Kathleen Kelly 4 , Guosheng Ren 1 , Qian Tao 1, 2 1 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China 2 Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong 3 Oncology Department, Suining Sichuan Center Hospital, Sichuan, China 4 Signal Transduction Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA Correspondence to: Guosheng Ren, email: rgs726@163.com Qian Tao, email: qtao@cuhk.edu.hk Keywords: DACT2, tumor suppressor, methylation, EMT, breast cancer Received: April 22, 2016 Accepted: September 14, 2016 Published: September 29, 2016 ABSTRACT Wnt signaling plays an important role in breast carcinogenesis. DAPPER2 (DACT2) functions as an inhibitor of canonical Wnt signaling and plays distinct roles in different cell contexts, with its role in breast tumorigenesis unclear. We investigated DACT2 expression in breast cancer cell lines and primary tumors, as well as its functions and molecular mechanisms. Results showed that DACT2 expression was silenced in 9/9 of cell lines. Promoter CpG methylation of DACT2 was detected in 89% (8/9) of cell lines, as well as in 73% (107/147) of primary tumors, but only in 20% (1/5) of surgical margin tissues and in none of normal breast tissues. Demethylation of BT549 and T47D cell lines with 5-aza-2’-deoxycytidine restored DACT2 expression along with promoter demethylation, suggesting that its downregulation in breast cancer is dependent on promoter methylation. Furthermore, ectopic expression of DACT2 induced breast cell apoptosis in vitro , and further inhibited breast tumor cell proliferation, migration and EMT, through antagonizing Wnt/β-catenin and Akt/GSK-3 signaling. Thus, these results demonstrate that DACT2 functions as a tumor suppressor for breast cancer but was frequently disrupted epigenetically in this cancer. |
| Databáze: | OpenAIRE |
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