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A unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells

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dc.contributor.author허만욱-
dc.date.accessioned2014-12-19T16:36:51Z-
dc.date.available2014-12-19T16:36:51Z-
dc.date.issued2012-
dc.identifier.issn1538-4047-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/89860-
dc.description.abstractPreviously, we demonstrated potent antineoplastic activity of a distinctive histone deacetylase inhibitor (HDACI), AR42, against chemoresistant CP70 ovarian cancer cells in vitro and in vivo. Here, in follow-up to that work, we explored AR42 global mechanisms-of-action by examining drug-associated, genome-wide microRNA and mRNA expression profiles, which differed from those of the well-studied HDACI vorinostat. Expression of microRNA genes in negative correlation with their "target" coding gene (mRNA) transcripts, and transcription factor genes with expression positively correlated with coding genes having their cognate binding sites, were identified and subjected to gene ontology analyses. Those evaluations showed AR42 gene expression patterns to negatively correlate with Wnt signaling (> 18-fold induction of SFRP1), the epithelial-to-mesenchymal transition (40% decreased ATF1), and cell cycle progression (33-fold increased 14-3-3σ). By contrast, AR42 transcriptome alterations correlated positively with extrinsic ("death receptor") apoptosis (> 2.3-fold upregulated DAPK) and favorable ovarian cancer histopathology and prognosis. Inhibition of Wnt signaling was experimentally validated by: (1) > 2.6-fold reduced Wnt reporter activity; and (2) 36% reduction in nuclear, activated β-catenin. Likely AR42 induction of multiple (type I or type II autophagic) cell death cascades was further supported by 57% decreased reliance upon reactive oxygen, increased mitochondrial membrane disruption, and caspase independence, as compared with vorinostat. Taken together, we demonstrate distinct antineoplastic pathway alterations, in aggressive ovarian cancer cells, following treatment with a promising HDACI, AR42. These combined computational and experimental approaches may also represent a straightforward means for mechanistic studies of other promising antineoplastics, and/or the identification of agents that may complement epigenetic therapies.-
dc.description.statementOfResponsibilityopen-
dc.relation.isPartOfCANCER BIOLOGY & THERAPY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHApoptosis/drug effects-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCluster Analysis-
dc.subject.MESHDrug Resistance, Neoplasm-
dc.subject.MESHFemale-
dc.subject.MESHGene Expression Profiling-
dc.subject.MESHGene Expression Regulation, Neoplastic/drug effects*-
dc.subject.MESHHistone Deacetylase Inhibitors/pharmacology*-
dc.subject.MESHHumans-
dc.subject.MESHMicroRNAs/genetics*-
dc.subject.MESHMolecular Sequence Annotation-
dc.subject.MESHOvarian Neoplasms/genetics*-
dc.subject.MESHOvarian Neoplasms/metabolism*-
dc.subject.MESHPhenylbutyrates/pharmacology*-
dc.subject.MESHRNA, Messenger/genetics-
dc.subject.MESHRNA, Messenger/metabolism-
dc.subject.MESHSignal Transduction/drug effects*-
dc.subject.MESHWnt Proteins/metabolism-
dc.titleA unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Biochemistry & Molecular Biology (생화학,분자생물학)-
dc.contributor.googleauthorCurt Balch-
dc.contributor.googleauthorKaleb Naegeli-
dc.contributor.googleauthorSeungyoon Nam-
dc.contributor.googleauthorBrett Ballard-
dc.contributor.googleauthorAlan Hyslop-
dc.contributor.googleauthorChristina Melki-
dc.contributor.googleauthorElizabeth Reilly-
dc.contributor.googleauthorMan-Wook Hur-
dc.contributor.googleauthorKenneth P. Nephew-
dc.identifier.doi22549158-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA04350-
dc.relation.journalcodeJ00435-
dc.identifier.eissn1555-8576-
dc.identifier.pmid22549158-
dc.subject.keywordepithelial-to-mesenchymal transition-
dc.subject.keywordhistone deacetylase inhibitor-
dc.subject.keywordmicroRNA-
dc.subject.keywordovarian cancer-
dc.subject.keywordWnt signaling-
dc.contributor.alternativeNameHur, Man Wook-
dc.contributor.affiliatedAuthorHur, Man Wook-
dc.citation.volume13-
dc.citation.number8-
dc.citation.startPage681-
dc.citation.endPage693-
dc.identifier.bibliographicCitationCANCER BIOLOGY & THERAPY, Vol.13(8) : 681-693, 2012-
dc.identifier.rimsid31948-
dc.type.rimsART-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers

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