CDH1 and SNAI1 are regulated by E7 from human papillomavirus types 16 and 18

Abstract

A common characteristic of cancer types associ- ated with viruses is the dysregulated expression of the CDH1 gene, 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 of CDH1 through two pathways: i) Epigenetic, including DNA methylation; and ii) Epigenetic-independent, including the induction of negative regulators of CDH1 expression, such as Snail family tran- scriptional repressor Snai1 and Snai2. To test this hypothesis, HPV16- and HPV18-positive cell lines were used to determine the methylation pattern of the CDH1 promoter and its expres- sion in association with its negative regulators. Different methylation frequencies were identified in the CDH1 promoter in HeLa (88.24%) compared with SiHa (17.65%) and Ca Ski (0%) cell lines. Significant differences in the expression of SNAI1 were observed between these cell lines, and an inverse association was identified between the expression levels of SNAI1 and CDH1. In addition, suppressing E7 not only increased the expression of CDH1, but notably decreased the expression of SNAI1 and modified the methylation pattern of the CDH1 promoter. These results suggested that the expres- sion of CDH1 was dependent on the expression of SNAI1 and was inversely associated with the expression of E7. The present results indicated that E7 from HPV16/18 regulated the expres- sion of CDH1 by the two following pathways in which Snai1 is involved: i) Hypermethylation of the CDH1 promoter region and increasing expression of SNAI1, as observed in HeLa; and ii) Hypomethylation of the CDH1 promoter region and expres- sion of SNAI1, as observed in SiHa. Therefore, the suppression of CDH1 and expression of SNAI1 may be considered to be biomarkers of metastasis in uterine cervical cancer.