200424

TET3

BACKGROUND: Abnormal DNA methylation/demethylation is recognized as a hallmark of cancer. TET (ten-eleven translocation) family members are novel DNA demethylation related proteins that dysregulate in multiple malignances. However, their effects on ovarian cancer remain to be elucidated. METHODS: The changes of TET family members during TGF-beta1-induced epithelial-mesenchymal transition (EMT) in SKOV3 and 3AO ovarian cancer cells were detected. TET3 was ectopically expressed in TGF-beta1-treated ovarian cancer cells to examine its effect on TGF-beta1-induced EMT phenotype. The downstream target of TET3 was further identified. Finally, the relationships of TET3 expression to clinic-pathological parameters of ovarian cancer were investigated with a tissue microarray using immunohistochemistry. RESULTS: TET3 was downregulated during TGF-beta1-initiatd epithelial-mesenchymal transition (EMT) in SKOV3 and 3AO ovarian cancer cells. Overexpression of TET3 reversed TGF-beta1-induced EMT phenotypes including the expression pattern of molecular markers (E-cadherin, Vimentin, N-cadherin, Snail) and migratory and invasive capabilities of ovarian cancer cells. miR-30d was identified as a downstream target of TET3, and TET3 overexpression resumed the demethylation status in the promoter region of miR-30d precursor gene, resulting in restoration of miR-30d (an EMT suppressor of ovarian cancer cells proven in our previous study) level in TGF-beta1-induced EMT. We further found that TET3 expression was decreased in ovarian cancer tissues, especially in serous ovarian cancers. The overall positivity of TET3 was inversely correlated with the grade of differentiation status of ovarian cancer. CONCLUSION: Our results revealed that TET3 acted as a suppressor of ovarian cancer by demethylating miR-30d precursor gene promoter to block TGF-beta1-induced EMT.

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-beta1-induced EMT-like process, and the knocking down of TET2 or TET3 induced this EMT-like process. A DNA demethylating agent antagonized the TGF-beta-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-beta induces the silencing of TET2 and TET3. Finally, the overexpression of the TET2 C-terminal sequence partially rescues the TGF-beta1-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-beta. As an effector, DNMT3A senses the TGF-beta signal and silences TET2 and TET3 promoters to induce the EMT-like process and metastasis in melanoma.