title: DNA hypomethylation-mediated overexpression of carbonic anhydrase 9 induces an aggressive phenotype in ovarian cancer cells.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Alterations in the DNA methylation profile of the CA9 promoter were correlated with a more aggressive phenotype in ovarian cancer cells.
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Hye Youn
authors.initials: HY
authors.lastname: Sung
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Seoul, Korea. goodmorning@ewha.ac.kr.
authors.forename: Woong
authors.initials: W
authors.lastname: Ju
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea. ahnj@ewha.ac.kr.
authors.forename: Jung-Hyuck
authors.initials: JH
authors.lastname: Ahn
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009374:Neoplasms, Experimental; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D000077209:Decitabine; D002256:Carbonic Anhydrases; D001374:Azacitidine
keywords: CA9; DNA methylation; Ovarian cancer; metastasis; mouse xenograft