Raza, U.Saatci, O.Uhlmann, S.Ansari, S. A.Eyüpoglu, E.Yurdusev, E.Mutlu, M.Ersan, P. G.Altundağ, M. K.Zhang, J. D.Dogan, H. T.Güler, G.Şahin, Ö.2018-04-122018-04-1220161949-2553http://hdl.handle.net/11693/36664Tumor 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.EnglishCTBP1EMTMiRNAsP53Therapy resistanceCarboxy terminal sequence binding protein 1Cyclin dependent kinase 1Cyclin dependent kinase inhibitor 1Cyclin dependent kinase inhibitor 1AGefitinibMembrane proteinMicroRNAMicroRNA 644aProtein NoxaProtein p21TamoxifenUnclassified drugAlcohol dehydrogenaseC-terminal binding proteinDNA binding proteinMicroRNAMIRN644 microRNA, humanProtein p53TP53 protein, humanAnimal experimentAnimal modelAnimal tissueArticleBreast cancerBreast cancer cell lineCancer growthCancer inhibitionCancer prognosisCancer resistanceCell proliferationCell survivalControlled studyCRISPR Cas systemDisease free survivalDown regulationEpithelial mesenchymal transitionFemaleG1 phase cell cycle checkpointGene identificationGene overexpressionGene targetingHumanHuman cellMetastasis potentialMouseNonhumanProtein targetingSite directed mutagenesisUpregulationAnimalApoptosisBreast tumorCancer transplantationCell cycleCell motionCell survivalDisease exacerbationDrug resistanceGene expression regulationGeneticsMCF-7 cell lineMetabolismMetastasisMortalityMutationNude mouseTumor cell lineTumor recurrenceAlcohol OxidoreductasesAnimalsApoptosisBreast NeoplasmsCell CycleCell Line, TumorCell MovementCell SurvivalDisease ProgressionDNA-Binding ProteinsDrug Resistance, NeoplasmEpithelial-Mesenchymal TransitionFemaleGene Expression Regulation, NeoplasticHumansMCF-7 CellsMiceMice, NudeMicroRNAsMutationNeoplasm MetastasisNeoplasm Recurrence, LocalNeoplasm TransplantationTumor Suppressor Protein p53Article10.18632/oncotarget.10489