The Function Of DNA Methyltransferases In TGF-β-induced EMT

The transforming growth factor-β (TGF-β) superfamily is a multifunctional cytokine that plays important roles during fetal development and adult tissue homeostasis. TGF-β signal is involved in various cellular functions, such as cell proliferation, apoptosis and differentiation. Thus, the dysregulation of TGF-β signaling transduction is implicated in diverse human diseases, such as cancer. At the initial stages of tumor development, activated TGF-P signaling suppresses tumor formation due to its ability of inhibiting cell growth and promoting cell apoptosis. During tumor progression, malignant tumor cells lose their ability to be growth arrested by TGF-β, TGF-β stimulation significantly promotes tumor invasion and metastasis, in which, TGF-β induced Epithelial-Mesenchymal Transition (EMT) plays a critical role.Epithelial-mesenchymal transition (EMT) happens when epithelial cells start to express mesenchymal specific proteins and lose cell polarity. By cell tight connection is bloken; the ability of migration is enhanced. EMT occurs during embryonic development, wound healing, fibrotic diseases and cancer pathogenesis. TGF-P promotes EMT by inducing the expression of several transcription regulators, such as δEF1, SIP1, and Snail.Appropriate DNA methylation is essential in development and proper cell function,and abnormalities of DNA methylation are observed in cancer. Generally, as compared with normal cells, the malignant cells show a global decrease in methylated CpG content. This phenomenon contributes to genomic instability and less frequently to activation of silenced oncogenes. DNA methylation is mediated by a family of highly related DNA methyltransferase enzymes, including DNMT1, DNMT3A and DNMT3B, which transfer a methyl group from S-adenosyl-Lmethionine to cytosine in CpG dinucleotide.In terms of the importance of TGF-β and aberrant DNA methylation in cancer, here we are trying to explore their relationship. Based on mass spectrum data, Smad proteins could interact with DNA methyltransferase. First, the interactions between Smad proteins and DNMT proteins were confirmed in vivo and in vitro. And then, we studied the role of DNMT proteins in TGF-β signaling transduction. Our results showed that DNMT3B and DNMT3L, but not DNMT3A reduced Smad transcriptional activity and suppressed TGF-β signaling. During TGF-β induced EMT, inducible expression of DNMT3B and DNMT3L, but not DNMT3A, could obviously down-regulate expression of mesenchymal specific proteins, such as Fibronectin, N-cadherin.