1. The miR-106b~25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300
- Author
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Ernesto Yagüe, Raoul Charles Coombes, Parmjit S. Jat, Yunhui Hu, D Xiong, Yuan Zhou, Selina Raguz, Ylenia Lombardo, M Yang, and Kaiyong Li
- Subjects
cancer stem cells ,Biochemistry & Molecular Biology ,TUMOR-CELLS ,Motility ,Breast Neoplasms ,Biology ,CISPLATIN RESISTANCE ,Transfection ,OVARIAN-CANCER ,Cancer stem cell ,Cell Movement ,Cell Line, Tumor ,microRNA ,Humans ,TERMINAL PROLIFERATION ARREST ,MULTIDRUG-RESISTANCE ,Molecular Biology ,11 Medical and Health Sciences ,Cellular Senescence ,Skin ,doxorubicin-induced senescence ,EP300 ,DRUG-RESISTANCE ,MESENCHYMAL TRANSITION ,Original Paper ,Science & Technology ,Cadherin ,EMT ,E-cadherin ,BREAST-CANCER CELLS ,Cell Biology ,06 Biological Sciences ,Fibroblasts ,Cadherins ,Phenotype ,Cell biology ,PROSTATE-CANCER ,MicroRNAs ,Cell Aging ,Doxorubicin ,Drug Resistance, Neoplasm ,Female ,Stem cell ,Cell aging ,Life Sciences & Biomedicine ,STEM-CELLS ,E1A-Associated p300 Protein - Abstract
Resistance to chemotherapeutic treatment, which is indirectly responsible for many cancer deaths, is normally associated with an aggressive phenotype including increased cell motility and acquisition of invasive properties. Here we describe how breast cancer cells overcome doxorubicin-induced senescence and become drug resistant by overexpression of the microRNA (miR)-106b~25 cluster. Although all three miRs in the cluster contribute to the generation of doxorubicin resistance, miR-25 is the major contributor to this phenotype. All three miRs in this cluster target EP300, a transcriptional activator of E-cadherin, resulting in cells acquiring a phenotype characteristic of cells undergoing epithelial-to-mesenchymal transition (EMT), including an increase in both cell motility and invasion, as well as the ability to proliferate after treatment with doxorubicin. These findings provide a novel drug resistance/EMT regulatory pathway controlled by the miR-106b~25 cluster by targeting a transcriptional activator of E-cadherin.
- Published
- 2013