Global Demethylation of Rat Chondrosarcoma Cells after Treatment with 5-Aza-2′-Deoxycytidine Results in Increased Tumorigenicity

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dc.contributorVirginia Techen
dc.contributor.authorHamm, Christopher A.en
dc.contributor.authorXie, Hehuang Daviden
dc.contributor.authorCosta, Fabricio F.en
dc.contributor.authorVanin, Elio F.en
dc.contributor.authorSeftor, Elisabeth A.en
dc.contributor.authorSredni, Simone T.en
dc.contributor.authorBischof, Jareden
dc.contributor.authorWang, Delien
dc.contributor.authorBonaldo, Maria F.en
dc.contributor.authorHendrix, Mary J. C.en
dc.contributor.authorSoares, Marcelo B.en
dc.date.accessed2014-05-01en
dc.date.accessioned2014-06-17T20:12:04Zen
dc.date.available2014-06-17T20:12:04Zen
dc.date.issued2009-12-17en
dc.description.abstractAbnormal patterns of DNA methylation are observed in several types of human cancer. While localized DNA methylation of CpG islands has been associated with gene silencing, the effect that genome-wide loss of methylation has on tumorigenesis is not completely known. To examine its effect on tumorigenesis, we induced DNA demethylation in a rat model of human chondrosarcoma using 5-aza-2-deoxycytidine. Rat specific pyrosequencing assays were utilized to assess the methylation levels in both LINEs and satellite DNA sequences following 5-aza-2-deoxycytidine treatment. Loss of DNA methylation was accompanied by an increase in invasiveness of the rat chondrosarcoma cells, in vitro, as well as by an increase in tumor growth in vivo. Subsequent microarray analysis provided insight into the gene expression changes that result from 5-aza-2-deoxycytidine induced DNA demethylation. In particular, two genes that may function in tumorigenesis, sox-2 and midkine, were expressed at low levels in control cells but upon 5-aza-2-deoxycytidine treatment these genes became overexpressed. Promoter region DNA analysis revealed that these genes were methylated in control cells but became demethylated following 5-aza-2-deoxycytidine treatment. Following withdrawal of 5-aza-2-deoxycytidine, the rat chondrosarcoma cells reestablished global DNA methylation levels that were comparable to that of control cells. Concurrently, invasiveness of the rat chondrosarcoma cells, in vitro, decreased to a level indistinguishable to that of control cells. Taken together these experiments demonstrate that global DNA hypomethylation induced by 5-aza-2-deoxycytidine may promote specific aspects of tumorigenesis in rat chondrosarcoma cells.en
dc.description.sponsorshipThe Everett/O'Connor Charitable Trust; Dr. Ralph and Marian C. Falk Medical Research Trust; Gus Foundation; The Maeve McNicholas Memorial Foundation; Medical Research Institute Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.identifier.citationHamm CA, Xie H, Costa FF, Vanin EF, Seftor EA, et al. (2009) Global Demethylation of Rat Chondrosarcoma Cells after Treatment with 5-Aza-2′-Deoxycytidine Results in Increased Tumorigenicity. PLoS ONE 4(12): e8340. doi:10.1371/journal.pone.0008340en
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0008340en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://hdl.handle.net/10919/48975en
dc.identifier.urlhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008340en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectCancer treatmenten
dc.subjectCarcinogenesisen
dc.subjectDNA methylationen
dc.subjectDNA transcriptionen
dc.subjectDrug therapyen
dc.subjectGene expressionen
dc.subjectMicroarraysen
dc.subjectPolymerase chain reactionen
dc.titleGlobal Demethylation of Rat Chondrosarcoma Cells after Treatment with 5-Aza-2′-Deoxycytidine Results in Increased Tumorigenicityen
dc.title.serialPLoS ONEen
dc.typeArticle - Refereeden

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