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

// Umar Raza 1 , Ozge Saatci 1 , Stefan Uhlmann 2 , Suhail A Ansari 1 , Erol Eyupoglu 1 , Emre Yurdusev 1 , Merve Mutlu 1 , Pelin Gulizar Ersan 1 , Mustafa Kadri Altundag 3 , Jitao David Zhang 4 , Hayriye Tatli Dogan 5 , Gulnur Guler 5 , Ozgur Şahin 1 1 Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey 2 Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland 3 Department of Medical Oncology, Hacettepe University Cancer Institute, 06410 Ankara, Turkey 4 Baumlihofstrasse 429, 4125 Riehen, Switzerland 5 Department of Pathology, Hacettepe University, 06410 Ankara, Turkey Correspondence to: Ozgur Şahin, email: sahinozgur@gmail.com Keywords: miRNAs, CTBP1, p53, EMT, therapy resistance Received: January 04, 2016      Accepted: June 26, 2016      Published: July 08, 2016 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.