The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer

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dc.citation.epage49877en_US
dc.citation.issueNumber31en_US
dc.citation.spage49859en_US
dc.citation.volumeNumber7en_US
dc.contributor.authorRaza, U.en_US
dc.contributor.authorSaatci, O.en_US
dc.contributor.authorUhlmann, S.en_US
dc.contributor.authorAnsari, S. A.en_US
dc.contributor.authorEyüpoglu, E.en_US
dc.contributor.authorYurdusev, E.en_US
dc.contributor.authorMutlu, M.en_US
dc.contributor.authorErsan, P. G.en_US
dc.contributor.authorAltundağ, M. K.en_US
dc.contributor.authorZhang, J. D.en_US
dc.contributor.authorDogan, H. T.en_US
dc.contributor.authorGüler, G.en_US
dc.contributor.authorŞahin, Ö.en_US
dc.date.accessioned2018-04-12T10:47:40Z
dc.date.available2018-04-12T10:47:40Z
dc.date.issued2016en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractTumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPRCas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a 'molecular switch' between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53- mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis.en_US
dc.identifier.doi10.18632/oncotarget.10489en_US
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/11693/36664
dc.language.isoEnglishen_US
dc.publisherImpact Journals LLCen_US
dc.relation.isversionofhttp://dx.doi.org/10.18632/oncotarget.10489en_US
dc.source.titleOncotargeten_US
dc.subjectCTBP1en_US
dc.subjectEMTen_US
dc.subjectMiRNAsen_US
dc.subjectP53en_US
dc.subjectTherapy resistanceen_US
dc.subjectCarboxy terminal sequence binding protein 1en_US
dc.subjectCyclin dependent kinase 1en_US
dc.subjectCyclin dependent kinase inhibitor 1en_US
dc.subjectCyclin dependent kinase inhibitor 1Aen_US
dc.subjectGefitiniben_US
dc.subjectMembrane proteinen_US
dc.subjectMicroRNAen_US
dc.subjectMicroRNA 644aen_US
dc.subjectProtein Noxaen_US
dc.subjectProtein p21en_US
dc.subjectTamoxifenen_US
dc.subjectUnclassified drugen_US
dc.subjectAlcohol dehydrogenaseen_US
dc.subjectC-terminal binding proteinen_US
dc.subjectDNA binding proteinen_US
dc.subjectMicroRNAen_US
dc.subjectMIRN644 microRNA, humanen_US
dc.subjectProtein p53en_US
dc.subjectTP53 protein, humanen_US
dc.subjectAnimal experimenten_US
dc.subjectAnimal modelen_US
dc.subjectAnimal tissueen_US
dc.subjectArticleen_US
dc.subjectBreast canceren_US
dc.subjectBreast cancer cell lineen_US
dc.subjectCancer growthen_US
dc.subjectCancer inhibitionen_US
dc.subjectCancer prognosisen_US
dc.subjectCancer resistanceen_US
dc.subjectCell proliferationen_US
dc.subjectCell survivalen_US
dc.subjectControlled studyen_US
dc.subjectCRISPR Cas systemen_US
dc.subjectDisease free survivalen_US
dc.subjectDown regulationen_US
dc.subjectEpithelial mesenchymal transitionen_US
dc.subjectFemaleen_US
dc.subjectG1 phase cell cycle checkpointen_US
dc.subjectGene identificationen_US
dc.subjectGene overexpressionen_US
dc.subjectGene targetingen_US
dc.subjectHumanen_US
dc.subjectHuman cellen_US
dc.subjectMetastasis potentialen_US
dc.subjectMouseen_US
dc.subjectNonhumanen_US
dc.subjectProtein targetingen_US
dc.subjectSite directed mutagenesisen_US
dc.subjectUpregulationen_US
dc.subjectAnimalen_US
dc.subjectApoptosisen_US
dc.subjectBreast tumoren_US
dc.subjectCancer transplantationen_US
dc.subjectCell cycleen_US
dc.subjectCell motionen_US
dc.subjectCell survivalen_US
dc.subjectDisease exacerbationen_US
dc.subjectDrug resistanceen_US
dc.subjectGene expression regulationen_US
dc.subjectGeneticsen_US
dc.subjectMCF-7 cell lineen_US
dc.subjectMetabolismen_US
dc.subjectMetastasisen_US
dc.subjectMortalityen_US
dc.subjectMutationen_US
dc.subjectNude mouseen_US
dc.subjectTumor cell lineen_US
dc.subjectTumor recurrenceen_US
dc.subjectAlcohol Oxidoreductasesen_US
dc.subjectAnimalsen_US
dc.subjectApoptosisen_US
dc.subjectBreast Neoplasmsen_US
dc.subjectCell Cycleen_US
dc.subjectCell Line, Tumoren_US
dc.subjectCell Movementen_US
dc.subjectCell Survivalen_US
dc.subjectDisease Progressionen_US
dc.subjectDNA-Binding Proteinsen_US
dc.subjectDrug Resistance, Neoplasmen_US
dc.subjectEpithelial-Mesenchymal Transitionen_US
dc.subjectFemaleen_US
dc.subjectGene Expression Regulation, Neoplasticen_US
dc.subjectHumansen_US
dc.subjectMCF-7 Cellsen_US
dc.subjectMiceen_US
dc.subjectMice, Nudeen_US
dc.subjectMicroRNAsen_US
dc.subjectMutationen_US
dc.subjectNeoplasm Metastasisen_US
dc.subjectNeoplasm Recurrence, Localen_US
dc.subjectNeoplasm Transplantationen_US
dc.subjectTumor Suppressor Protein p53en_US
dc.titleThe miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast canceren_US
dc.typeArticleen_US

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