Work

Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma

Year: 2016

Type: article

Abstract: // Fuxing Gong 1, 2, 3 , Yu Guo 1, 3 , Yiqian Niu 1, 3 , Jiawei Jin 1 , Xiaojuan Zhang 1 , Xiaoqian Shi 1, 3 , Limeng Zhang 2 , Runting Li 2 , Longxin Chen 2 , Runlin Z. Ma 1, 2, 3 1 State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China 2 Zhengzhou City Key Laboratory of Molecular Biology, Zhengzhou Normal University, Zhengzhou 450044, China 3 University of the Chinese Academy of Sciences, Beijing 100101, China Correspondence to: Runlin Z. Ma, email: [email protected] Keywords: TGF-β, TET, DNMT3A, EMT, Melanoma Received: June 03, 2016 Accepted: November 04, 2016 Published: November 12, 2016 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.13324