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

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...

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Autores principales: Raza, Umar, Saatci, Özge, Uhlmann, Stefan, Ansari, Suhail A, Eyüpoğlu, Erol, Yurdusev, Emre, Mutlu, Merve, Ersan, Pelin Gülizar, Altundağ, Mustafa Kadri, Zhang, Jitao David, Doğan, Hayriye Tatlı, Güler, Gülnur, Şahin, Özgür
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226553/
https://www.ncbi.nlm.nih.gov/pubmed/27409664
http://dx.doi.org/10.18632/oncotarget.10489
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author Raza, Umar
Saatci, Özge
Uhlmann, Stefan
Ansari, Suhail A
Eyüpoğlu, Erol
Yurdusev, Emre
Mutlu, Merve
Ersan, Pelin Gülizar
Altundağ, Mustafa Kadri
Zhang, Jitao David
Doğan, Hayriye Tatlı
Güler, Gülnur
Şahin, Özgür
author_facet Raza, Umar
Saatci, Özge
Uhlmann, Stefan
Ansari, Suhail A
Eyüpoğlu, Erol
Yurdusev, Emre
Mutlu, Merve
Ersan, Pelin Gülizar
Altundağ, Mustafa Kadri
Zhang, Jitao David
Doğan, Hayriye Tatlı
Güler, Gülnur
Şahin, Özgür
author_sort Raza, Umar
collection PubMed
description 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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spelling pubmed-52265532017-01-18 The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer Raza, Umar Saatci, Özge Uhlmann, Stefan Ansari, Suhail A Eyüpoğlu, Erol Yurdusev, Emre Mutlu, Merve Ersan, Pelin Gülizar Altundağ, Mustafa Kadri Zhang, Jitao David Doğan, Hayriye Tatlı Güler, Gülnur Şahin, Özgür Oncotarget Research Paper 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. Impact Journals LLC 2016-07-08 /pmc/articles/PMC5226553/ /pubmed/27409664 http://dx.doi.org/10.18632/oncotarget.10489 Text en Copyright: © 2016 Raza et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Raza, Umar
Saatci, Özge
Uhlmann, Stefan
Ansari, Suhail A
Eyüpoğlu, Erol
Yurdusev, Emre
Mutlu, Merve
Ersan, Pelin Gülizar
Altundağ, Mustafa Kadri
Zhang, Jitao David
Doğan, Hayriye Tatlı
Güler, Gülnur
Şahin, Özgür
The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer
title The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer
title_full The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer
title_fullStr The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer
title_full_unstemmed The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer
title_short The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer
title_sort mir-644a/ctbp1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226553/
https://www.ncbi.nlm.nih.gov/pubmed/27409664
http://dx.doi.org/10.18632/oncotarget.10489
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