TET1 Inhibits Ovarian Cancer Cell Proliferation By Inducing RASSF5 Expression

Epithelial ovarian cancer is the most lethal of the gynecologic malignancies and is the fifth most common cause of cancer death for women in the United States.Due to the internal localization of the ovaries,the lack of specific symptoms,and a lack of an effective screening method,ovarian cancer usually remains undetected until it has reached an advanced stage.In nearly 70%of patients who present with late-stage disease,it has already spread to other organs in the abdominal cavity and their 5-year survival remains at only 30%.DNA hypermethylation at the promoters of tumour-suppressor genes is tightly correlated with their transcriptional repression,and is recognized as the hallmark of majority of cancers.Ten eleven translocation(TET)enzymes catalyse the oxidative reactions of 5-mehtycytosin(5mC)to promote the DNA demethylation process.Tet1 downregulation has been shown to promote malignancy in breast and colon cancers.However,TET1’s roles in ovarian cancer cell survival are unknown.In this study,we found that Tetl and 5hmC were decreased in human ovarian cancer tissues and cells.TET1 and CUL4-DDB1 ubiquitin ligase complex regulated 5hmC levels in ovarian cancer cell lines.A role of TET1 in ovarian cancer cell proliferation were examined.Overexpression of TET1 repressed multiple ovarian cancer cell lines’proliferation and colony formation,whereas TET1 depletion by RNA interference had the opposite effect in vitro and in vivo.Upregulation of TET1 induced Rassf5’ promoter demethylation resulting in tumor repression.Thus the DNA hydroxymethylation mediated by TET1 is a key process of tumor growth.These results provide new insights for understanding how ovarian cancer cells escape cellular controls.