Methyl-CpG-binding protein 2 drives the Furin/TGF-β1/Smad axis to promote epithelial–mesenchymal transition in pancreatic cancer cells

Abstract

Methyl-CpG-binding protein 2 (MeCP2) has been characterized as an oncogene in several types of cancer. However, its precise role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Hence, this study aimed to evaluate the potential role of MeCP2 in pancreatic cancer progression. We found that MeCP2 was upregulated in pancreatic cancer tissues, enhanced migration, invasion, and proliferation in pancreatic cancer cells, and promoted tumorigenesis. Further evidence revealed that MeCP2 remarkably increased the mesenchymal markers vimentin, N-cadherin, and Snail, and downregulated the expression of the epithelial markers E-cadherin and ZO-1, indicating that MeCP2 promotes epithelial-mesenchymal transition (EMT). In addition, we found that MeCP2 upregulated the expression of Furin, activated TGF-β1, and increased the levels of p-Smad2/3. Importantly, we demonstrated that MeCP2, as a coactivator, enhanced Smad3 binding to the furin promoter to improve its transcription. Therefore, MeCP2/Smads drive the expression of Furin to activate TGF-β1, and in turn, phosphorylate Smad2/3, which forms a positive-feedback axis to promote EMT in pancreatic cancer cells.

RETRACTED: MeCP2 drives hepatocellular carcinoma progression via enforcing HOXD3 promoter methylation and expression through the HB‐EGF/EGFR pathway

“…Luo and Ge [ 33 ] showed that MeCP2 promotes colorectal cancer metastasis by modulating ZEB1 transcription. In pancreatic cancer, MeCP2 drove the Furin/TGF‐β1/Smad axis to increase epithelial–mesenchymal transition in pancreatic cancer cells [ 34 ]. In our present study, TCGA and GTEX data revealed that MeCP2 expression was remarkably higher in HCC tissues and was correlated with patients' survival rate; these results were confirmed in our 36 paired HCC tissues.…”

Methyl CpG binding protein 2 promotes colorectal cancer metastasis by regulating N6‐methyladenosine methylation through methyltransferase‐like 14

“…Although recent experimental evidence has shown that MeCP2 contributes to cancer proliferation and metastasis, 31,46,47 the biological mechanism of MeCP2 on carcinogenesis is still unclear.…”

“…Although recent experimental evidence has shown that MeCP2 contributes to cancer proliferation and metastasis, 31,46,47 the biological mechanism of MeCP2 on carcinogenesis is still unclear. Here, we found a novel mechanism through indirect influence on m 6 A methylation modification.…”

An Overview of Epigenetic Methylation in Pancreatic Cancer Progression

“…But their roles in in PC are not well understood except a few members ( 35 ). MeCP is the first identified MBD domain-containing protein and considered to be an oncogene in PC, promoting EMT in PC cells ( 36 ). However, MBD3 plays a suppressive role in PC.…”