Oncotarget

Research Papers:

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

Umar Raza, Özge Saatci, Stefan Uhlmann, Suhail A Ansari, Erol Eyüpoğlu, Emre Yurdusev, Merve Mutlu, Pelin Gülizar Ersan, Mustafa Kadri Altundağ, Jitao David Zhang, Hayriye Tatlı Doğan, Gülnur Güler and Özgür Şahin _

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Oncotarget. 2016; 7:49859-49877. https://doi.org/10.18632/oncotarget.10489

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Abstract

Umar Raza1, Özge Saatci1, Stefan Uhlmann2, Suhail A Ansari1, Erol Eyüpoğlu1, Emre Yurdusev1, Merve Mutlu1, Pelin Gülizar Ersan1, Mustafa Kadri Altundağ3, Jitao David Zhang4, Hayriye Tatlı Doğan5, Gülnur Güler5, Özgür Şahin1

1Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey

2Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland

3Department of Medical Oncology, Hacettepe University Cancer Institute, 06410 Ankara, Turkey

4Bäumlihofstrasse 429, 4125 Riehen, Switzerland

5Department of Pathology, Hacettepe University, 06410 Ankara, Turkey

Correspondence to:

Özgür 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.


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