title: The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer.
abstract: 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 CRISPR-Cas9 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.
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Umar
authors.initials: U
authors.lastname: Raza
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Özge
authors.initials: Ö
authors.lastname: Saatci
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlmann
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Suhail A
authors.initials: SA
authors.lastname: Ansari
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Erol
authors.initials: E
authors.lastname: Eyüpoğlu
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Emre
authors.initials: E
authors.lastname: Yurdusev
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Merve
authors.initials: M
authors.lastname: Mutlu
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Pelin Gülizar
authors.initials: PG
authors.lastname: Ersan
authors.affiliation: Department of Medical Oncology, Hacettepe University Cancer Institute, 06410 Ankara, Turkey.
authors.forename: Mustafa Kadri
authors.initials: MK
authors.lastname: Altundağ
authors.affiliation: Bäumlihofstrasse 429, 4125 Riehen, Switzerland.
authors.forename: Jitao David
authors.initials: JD
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Hacettepe University, 06410 Ankara, Turkey.
authors.forename: Hayriye Tatlı
authors.initials: HT
authors.lastname: Doğan
authors.affiliation: Department of Pathology, Hacettepe University, 06410 Ankara, Turkey.
authors.forename: Gülnur
authors.initials: G
authors.lastname: Güler
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Özgür
authors.initials: Ö
authors.lastname: Şahin
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009368:Neoplasm Transplantation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C579242:MIRN644 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein
keywords: CTBP1; EMT; miRNAs; p53; therapy resistance