Methylomics analysis identifies epigenetically silenced genes and implies an activation of β‐catenin signaling in cervical cancer

Abstract

Using DNA methylation biomarkers in cancer detection is a potential direction in clinical testing. Some methylated genes have been proposed for cervical cancer detection; however, more reliable methylation markers are needed. To identify new hypermethylated genes in the discovery phase, we compared the methylome between a pool of DNA from normal cervical epithelium (n 5 19) and a pool of DNA from cervical cancer tissues (n 5 38) using a methylation bead array. We integrated the differentially methylated genes with public gene expression databases, which resulted in 91 candidate genes. Based on gene expression after demethylation treatment in cell lines, we confirmed 61 genes for further validation. In the validation phase, quantitative MSP and bisulfite pyrosequencing were used to examine their methylation level in an independent set of clinical samples. Fourteen genes, including ADRA1D, AJAP1, COL6A2, EDN3, EPO, HS3ST2, MAGI2, POU4F3, PTGDR, SOX8, SOX17, ST6GAL2, SYT9, and ZNF614, were significantly hypermethylated in CIN31 lesions. The sensitivity, specificity, and accuracy of POU4F3 for detecting CIN31 lesions were 0.88, 0.82, and 0.85, respectively. A bioinformatics function analysis revealed that AJAP1, EDN3, EPO, MAGI2, and SOX17 were potentially implicated in b-catenin signaling, suggesting the epigenetic dysregulation of this signaling pathway during cervical cancer development. The concurrent methylation of multiple genes in cancers and in subsets of precancerous lesions suggests the presence of a driver of methylation phenotype in cervical carcinogenesis. Further validation of these new genes as biomarkers for cervical cancer screening in a larger population-based study is warranted.

Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach

“…It interacts with E-cadherin–β-catenin complexes in polarized epithelial cells. The methylation of AJAP1 may lead to the release of β-catenin and the activation of Wnt signaling [22]. AJAP1 expression has been recently reported to be reduced in HCC compared with non-cancerous liver tissues and to be associated with hypermethylation of the AJAP1 promoter.…”

MAGI-2 scaffold protein is critical for kidney barrier function

“…More recent deep sequencing studies have found translocations involving MAGI-2 and PTEN in human prostate tumors (21), and genetic deletion and rearrangement of MAGI-2 in a human melanoma cell line (22). MAGI-2 has also been identified as a target of miRNAs that are upregulated in tumors (23,24), and is hypermethylated in cervical cancer tissue (25).…”

Endogenous AJAP1 associates with the cytoskeleton and attenuates angiogenesis in endothelial cells

“…In this context, glioma cells stably overexpressing AJAP1 show a reduced migratory capacity compared to wild-type cells suggesting that AJAP1 actually has an inhibiting effect on cell migration (McDonald et al, 2006). Overexpression of AJAP1 in oligodendroglioma cell lines indicates that AJAP1 localizes at the adherens junctions, where it could interact with β-catenin (Chen et al, 2014; Zeng et al, 2014). In surgical sections of diffuse astrocytoma, AJAP1 localizes at the cell membrane, whereas in oligodendroglioma sections AJAP1 is not detectable at all (Zeng et al, 2014).…”