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Epigenetic Silencing of TET2 and TET3 Induces an EMT-like Process in Melanoma
Fuxing Gong, Yu Guo, Yiqian Niu, Jiawei Jin, Xiaojuan Zhang, Xiaoqian Shi, Limeng Zhang, Runting Li, Longxin Chen, Runlin Z. Ma
Oncotarget
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.
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DOI:10.18632/oncotarget.13324 |
论文题目: |
Epigenetic Silencing of TET2 and TET3 Induces an EMT-like Process in Melanoma |
英文论文题目: |
Epigenetic Silencing of TET2 and TET3 Induces an EMT-like Process in Melanoma |
第一作者: |
Fuxing Gong, Yu Guo, Yiqian Niu, Jiawei Jin, Xiaojuan Zhang, Xiaoqian Shi, Limeng Zhang, Runting Li, Longxin Chen, Runlin Z. Ma |
英文第一作者: |
Fuxing Gong, Yu Guo, Yiqian Niu, Jiawei Jin, Xiaojuan Zhang, Xiaoqian Shi, Limeng Zhang, Runting Li, Longxin Chen, Runlin Z. Ma |
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2016-11-25 |
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摘要: |
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. |
英文摘要: |
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. |
刊物名称: |
Oncotarget |
英文刊物名称: |
Oncotarget |
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其它备注: |
Fuxing Gong, Yu Guo, Yiqian Niu, Jiawei Jin, Xiaojuan Zhang, Xiaoqian Shi, Limeng Zhang, Runting Li, Longxin Chen, Runlin Z. Ma. Epigenetic Silencing of TET2 and TET3 Induces an EMT-like Process in Melanoma. Oncotarget. DOI:10.18632/oncotarget.13324 |
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