title: DACT2 silencing by promoter CpG methylation disrupts its regulation of epithelial-to-mesenchymal transition and cytoskeleton reorganization in breast cancer cells.
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.
authors.affiliation: Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Tingxiu
authors.initials: T
authors.lastname: Xiang
authors.affiliation: 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.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Oncology Department, Suining Sichuan Center Hospital, Sichuan, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ying
authors.affiliation: Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Junhao
authors.initials: J
authors.lastname: Mu
authors.affiliation: Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Peng
authors.affiliation: Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yixiao
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Signal Transduction Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Oberst
authors.affiliation: Signal Transduction Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kelly
authors.affiliation: Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Ren
authors.affiliation: Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.|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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics*; D000073399:DNA Demethylation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D000077209:Decitabine; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C478653:DACT2 protein, human; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D000077209:Decitabine; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D001374:Azacitidine
keywords: DACT2; EMT; breast cancer; methylation; tumor suppressor