Melanoma is the most dangerous type of skin cancer in human. It develops from the pigment-containing cells known as melanocytes
. Epithelial-Mesenchymal Transition (EMT) is a critical step in the progression of cancer. Malignant melanoma metastasizes through an EMT-like process. Ten-eleven translocation (TET) enzymes are down regulated in melanoma. However, their roles in the progression and the EMT-like process of melanoma are not understood clearly.
Researchers from Prof. MA Runlin’s lab at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, revealed that epigenetic silencing of TET2 and TET3 induces an EMT-like process to promote the progression of melanoma.
They found that the expression levels of TET2 and TET3 are significantly decreased in the Transforming growth factor-β1(TGF-β1)-induced EMT-like process, and shRNA-mediated knockdown of TET2 or TET3 induced the EMT-like process and up regulated the expression of several critical EMT transcriptional regulators. Mechanistically, TGF-β1 stimulated endogenous DNA Methyltransferase 3A/3B (DNMT3A/3B) expression, while depletion of DNMT3A activated TET2 and TET3 expression. ChIP-PCR experiment further showed that the recruitment of DNMT3A to TET2 and TET3 promoters was enhanced by TGF-β treatment. Moreover, the overexpression of the TET2 C-terminal domain partially suppressed the TGF-β1-induced EMT-like process in vitro and inhibited tumor growth and metastasis in vivo.
This research showed for the first time that the epigenetic silencing of TET2 and TET3 by DNA methylation is one mechanism by which TGF-β induces an EMT-like process.
“It is possible that EMT process of other cancer cell may also follow the same or similar mechanisms”, said Dr. MA and this hypothesis is what MA’s lab is currently working on.
This study entitled “Epigenetic Silencing of TET2 and TET3 Induces an EMT-like Process in Melanoma” was published online on Oncotarget, a prestigious international journal focused on researches of human cancer (doi: 10.18632/oncotarget.13324).
This work was supported by the National Basic Research Program of China and the National Natural Science Foundation of China.
Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma. (Image by IGDB)
A.Over expression of TET2 inhibits melanoma growth;
B.Over expression of TET2 inhibits melanoma metastasis;
C.DNMT3A senses the TGF-β signal and silences TET2 and TET3 promoters to induce the EMT-like process and metastasis in melanoma.
Dr. MA Runlin