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

Raza, U.
Saatci, O.
Uhlmann, S.
Ansari, S. A.
Eyüpoglu, E.
Yurdusev, E.
Mutlu, M.
Ersan, P. G.
Altundağ, M. K.
Zhang, J. D.
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Impact Journals LLC
49859 - 49877
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Tumor 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.

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CTBP1 , EMT , MiRNAs , P53 , Therapy resistance , Carboxy terminal sequence binding protein 1 , Cyclin dependent kinase 1 , Cyclin dependent kinase inhibitor 1 , Cyclin dependent kinase inhibitor 1A , Gefitinib , Membrane protein , MicroRNA , MicroRNA 644a , Protein Noxa , Protein p21 , Tamoxifen , Unclassified drug , Alcohol dehydrogenase , C-terminal binding protein , DNA binding protein , MicroRNA , MIRN644 microRNA, human , Protein p53 , TP53 protein, human , Animal experiment , Animal model , Animal tissue , Article , Breast cancer , Breast cancer cell line , Cancer growth , Cancer inhibition , Cancer prognosis , Cancer resistance , Cell proliferation , Cell survival , Controlled study , CRISPR Cas system , Disease free survival , Down regulation , Epithelial mesenchymal transition , Female , G1 phase cell cycle checkpoint , Gene identification , Gene overexpression , Gene targeting , Human , Human cell , Metastasis potential , Mouse , Nonhuman , Protein targeting , Site directed mutagenesis , Upregulation , Animal , Apoptosis , Breast tumor , Cancer transplantation , Cell cycle , Cell motion , Cell survival , Disease exacerbation , Drug resistance , Gene expression regulation , Genetics , MCF-7 cell line , Metabolism , Metastasis , Mortality , Mutation , Nude mouse , Tumor cell line , Tumor recurrence , Alcohol Oxidoreductases , Animals , Apoptosis , Breast Neoplasms , Cell Cycle , Cell Line, Tumor , Cell Movement , Cell Survival , Disease Progression , DNA-Binding Proteins , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Mice , Mice, Nude , MicroRNAs , Mutation , Neoplasm Metastasis , Neoplasm Recurrence, Local , Neoplasm Transplantation , Tumor Suppressor Protein p53
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