Cdh1 And Snai1 Are Regulated By E7 From Human Papillomavirus Types 16 And 18

A common characteristic of cancer types associated with viruses is the dysregulated expression of theCDH1gene, which encodes E-cadherin, in general by activation of DNA methyltransferases (Dnmts). In cervical cancer, E7 protein from high risk human papillomaviruses (HPVs) has been demonstrated to interact with Dnmt1 and histone deacetylase type 1 (HDAC1). The present study proposed that E7 may regulate the expression ofCDH1through two pathways: i) Epigenetic, including DNA methylation; and ii) Epigenetic-independent, including the induction of negative regulators ofCDH1expression, such as Snail family transcriptional repressor Snai1 and Snai2. To test this hypothesis, HPV16- and HPV18-positive cell lines were used to determine the methylation pattern of theCDH1promoter and its expression in association with its negative regulators. Different methylation frequencies were identified in theCDH1promoter in HeLa (88.24%) compared with SiHa (17.65%) and Ca Ski (0%) cell lines. Significant differences in the expression ofSNAI1were observed between these cell lines, and an inverse association was identified between the expression levels ofSNAI1andCDH1. In addition, suppressing E7 not only increased the expression ofCDH1, but notably decreased the expression ofSNAI1and modified the methylation pattern of theCDH1promoter. These results suggested that the expression ofCDH1was dependent on the expression ofSNAI1and was inversely associated with the expression of E7. The present results indicated that E7 from HPV16/18 regulated the expression ofCDH1by the two following pathways in which Snai1 is involved: i) Hypermethylation of theCDH1promoter region and increasing expression ofSNAI1, as observed in HeLa; and ii) Hypomethylation of theCDH1promoter region and expression ofSNAI1, as observed in SiHa. Therefore, the suppression ofCDH1and expression ofSNAI1may be considered to be biomarkers of metastasis in uterine cervical cancer.