The Role And Mechanism Of SENP1 In IL-4 Induced Emt Of Human Colorectal Cancer Cells

The epithelial-mesenchymal transition(EMT) is a biological process enabling epithelial cells to assume a mesenchymal cell phenotype, which includes decrease of E-cadherin and dysregulated expression of Vimentin. EMT is particularly important during embryonic development, tissue regeneration and cancer metastasis. Cancer-associated EMT is triggered by multiple factors from tumor microenvironment, such as hypoxia and cytokines(TGF-?, IL6 and TNF-?). However, the underlying mechanism of cytokines-induced EMT remians poorly understood. In this study, we found that colorectal cancer tissues show high SENP1 expression than adjacent normal tissues in IHC analysis. Moreover, SENP1 expression positively correlates with the clinical stage of tumor samples, increased SENP levels indicate high potential for metastasis. In colorectal adenocarcinoma DLD-1 cells, overexpression of SENP1 promotes cell migration in transwell assay and wound-healing assay, while knocking-down SENP1 inhibits the migration of DLD-1 cells. IL-4 is a positive regulator of SENP1 expression. IL-4 induces EMT and increase migration of DLD-1 cells. In DLD-1 cells stably knocking-down SENP1, IL-4 treatment has no effect on the expression of E-cadherin or Vimentin, consequently cell migration ability is not altered, suggesting IL-4 induced EMT is mediated by SENP1 in colorectal cancer. We further found that SENP1 induce EMT through de-SUMOylating STAT6, upregualting its phosphorylation and promoting its transcriptional activity. IL-4 treament increases SENP1 expression through activates STAT6 and enhance its binding to SENP1 promoter in dual luciferase reporter assay. Altogether, our study investigates the regulation of colorectal cancer metastasis by SENP1 and suggests a positive-feedback loop of STAT6/SENP1 in IL-4 induced EMT.