The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer
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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.
Carboxy terminal sequence binding protein 1
Cyclin dependent kinase 1
Cyclin dependent kinase inhibitor 1
Cyclin dependent kinase inhibitor 1A
C-terminal binding protein
DNA binding protein
MIRN644 microRNA, human
TP53 protein, human
Breast cancer cell line
CRISPR Cas system
Disease free survival
Epithelial mesenchymal transition
G1 phase cell cycle checkpoint
Site directed mutagenesis
Gene expression regulation
MCF-7 cell line
Tumor cell line
Cell Line, Tumor
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Neoplasm Recurrence, Local
Tumor Suppressor Protein p53
Published Version (Please cite this version)http://dx.doi.org/10.18632/oncotarget.10489
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