DNA Hypomethylation-Mediated Overexpression of Carbonic Anhydrase 9 Induces an Aggressive Phenotype in Ovarian Cancer Cells.
10.3349/ymj.2014.55.6.1656
- Author:
Hye Youn SUNG
1
;
Woong JU
;
Jung Hyuck AHN
Author Information
1. Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea. ahnj@ewha.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Ovarian cancer;
metastasis;
mouse xenograft;
CA9;
DNA methylation
- MeSH:
Animals;
Azacitidine/*analogs & derivatives/pharmacology;
Carbonic Anhydrases/metabolism;
*DNA Methylation;
Female;
Gene Expression Regulation, Neoplastic/*drug effects;
Humans;
Mice;
Neoplasm Invasiveness/genetics;
Neoplasm Metastasis/genetics/*pathology;
Neoplasms, Experimental;
Neoplasms, Glandular and Epithelial/genetics/*metabolism/pathology;
Ovarian Neoplasms/genetics/*metabolism/pathology;
Phenotype;
Promoter Regions, Genetic;
RNA, Messenger/metabolism
- From:Yonsei Medical Journal
2014;55(6):1656-1663
- CountryRepublic of Korea
- Language:English
-
Abstract:
PURPOSE: Both genetic and epigenetic alterations can lead to abnormal expression of metastasis-regulating genes in tumor cells. Recent studies suggest that aberrant epigenetic alterations, followed by differential gene expression, leads to an aggressive cancer cell phenotype. We examined epigenetically regulated genes that are involved in ovarian cancer metastasis. MATERIALS AND METHODS: We developed SK-OV-3 human ovarian carcinoma cell xenografts in mice. We compared the mRNA expression and DNA methylation profiles of metastatic tissues to those of the original SK-OV-3 cell line. RESULTS: Metastatic implants showed increased mRNA expression of the carbonic anhydrase 9 (CA9) gene and hypomethylation at CpG sites in the CA9 promoter. Treatment of wild-type SK-OV-3 cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reduced methylation of the CA9 promoter and increased CA9 mRNA expression. Eight CpGs, which were located at positions -197, -74, -19, -6, +4, +13, +40, and +86, relative to the transcription start site, were hypomethylated in metastatic tumor implants, compared to that of wild-type SK-OV-3. Overexpression of CA9 induced an aggressive phenotype, including increased invasiveness and migration, in SK-OV-3 cells. CONCLUSION: Alterations in the DNA methylation profile of the CA9 promoter were correlated with a more aggressive phenotype in ovarian cancer cells.
