title: Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma.
abstract: Epithelial-Mesenchymal Transition (EMT) is a critical step in the progression of cancer. Malignant melanoma, a cancer developed from pigmented melanocytes, metastasizes through an EMT-like process. Ten-eleven translocation (TET) enzymes, catalyzing the conversion of 5-methylcytosine (5mC) to 5-hydroxylmethylcytosine (5-hmC), are down regulated in melanoma. However, their roles in the progression and the EMT-like process of melanoma are not fully understood. Here we report that DNA methylation induced silencing of TET2 and TET3 are responsible for the EMT-like process and the metastasis of melanoma. TET2 and TET3 are down regulated in the TGF-β1-induced EMT-like process, and the knocking down of TET2 or TET3 induced this EMT-like process. A DNA demethylating agent antagonized the TGF-β-induced suppression of TET2 and TET3. Furthermore, a ChIP analysis indicated that enhanced recruitment of DNMT3A (DNA Methyltransferase 3A) is the mechanism by which TGF-β induces the silencing of TET2 and TET3. Finally, the overexpression of the TET2 C-terminal sequence partially rescues the TGF-β1-induced EMT-like process in vitro and inhibits tumor growth and metastasis in vivo. Hence, our data suggest an epigenetic circuitry that mediates the EMT activated by TGF-β. As an effector, DNMT3A senses the TGF-β signal and silences TET2 and TET3 promoters to induce the EMT-like process and metastasis in melanoma.
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Zhengzhou City Key Laboratory of Molecular Biology, Zhengzhou Normal University, Zhengzhou 450044, China.|University of the Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fuxing
authors.initials: F
authors.lastname: Gong
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|University of the Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|University of the Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Niu
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Jin
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|University of the Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Shi
authors.affiliation: Zhengzhou City Key Laboratory of Molecular Biology, Zhengzhou Normal University, Zhengzhou 450044, China.
authors.forename: Limeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Zhengzhou City Key Laboratory of Molecular Biology, Zhengzhou Normal University, Zhengzhou 450044, China.
authors.forename: Runting
authors.initials: R
authors.lastname: Li
authors.affiliation: Zhengzhou City Key Laboratory of Molecular Biology, Zhengzhou Normal University, Zhengzhou 450044, China.
authors.forename: Longxin
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Zhengzhou City Key Laboratory of Molecular Biology, Zhengzhou Normal University, Zhengzhou 450044, China.|University of the Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Runlin Z
authors.initials: RZ
authors.lastname: Ma
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D000073399:DNA Demethylation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000077209:Decitabine; D049308:Dioxygenases / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D000077209:Decitabine; C578792:TET3 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D001374:Azacitidine
keywords: DNMT3A; EMT; Melanoma; TET; TGF-β