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 EMTlike 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.