Dna Hypomethylation-Mediated Activation Of Cancer-Testis/Germline Antigen Pote Is Associated With Disease Progression In Human Epithelial Ovarian Cancer.

Introduction: POTE (Prostate, Ovary, Testis, Placenta genes) are autosomal, non-X Testis/Germline antigen, located on pericentromeric heterochromatin region. POTE family is consisting of 13 paralogous which are dispersed on eight different chromosomes, whose members are expressed in epithelial ovarian cancer (EOC) and solid tumor malignancies. DNA methylation changes are common in EOC, and frequently consist of loss of DNA methylation genome-wide at specific repetitive DNA elements, including LINE-1, and at pericentromeric regions. Objective: Determine whether DNA methylation changes or other epigenetic mechanisms regulate POTE expression and to define the potential functional contribution of POTE expressions in ovarian cancer. Materials and Methods: Affymetrix HG 1.0ST microarrays and RT-qPCR were used to determine POTE gene expression in normal ovary and EOC tumors. DNA methylation status of POTE and neighboring pericentromeric regions, where POTE genes reside, was determined by using sodium bisulfite pyrosequencing. Cell proliferation, cell migration, and cell invasion were determined following POTE knockdown or overexpression. Results: POTE expression levels were highly elevated in EOC tumors showing global hypomethylation of LINE1 elements, as compared to EOC tumors with hypermethylation of LINE1 elements, linking global DNA methylation status to POTE expression. Methylation of pericentromeric DNA, as determined using NBL2 pyrosequencing, was also closely linked to POTE expression and methylation status. POTE gene knockdown in EOC cell lines had minimal impact on cell proliferation and apoptosis, but resulted in significantly reduced cell migration and cell invasion. Conclusion: POTE hypomethylation and expression correlate with poor prognosis in EOC. These data establish a specific oncogenic role for DNA hypomethylation in EOC, and reveal POTEs as biomarkers and therapeutic targets in this malignancy. [ABSTRACT FROM AUTHOR]