A miR-200c/141-BMI1 autoregulatory loop regulates oncogenic activity of BMI1 in cancer cells
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Manjari Dimri1, Mingu Kang1, Goberdhan P. Dimri1
1Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA
Goberdhan P. Dimri, e-mail: firstname.lastname@example.org
Manjari Dimri, e-mail: email@example.com
Keywords: breast cancer, senescence, BMI1, microRNA, miR-141
Received: February 04, 2016 Accepted: March 31, 2016 Published: April 18, 2016
MicroRNAs (miRNAs) are known to function as oncomiRs or tumor suppressors and are important noncoding RNA regulators of oncogenesis. The miR-200c/141 locus on chromosome 12 encodes miR-200c and miR-141, two members of the miR-200 family, which have been shown to function as tumor suppressive miRNAs by targeting multiple oncogenic factors such as polycomb group protein BMI1. Here, we show that BMI1 reciprocally functions as a transcriptional repressor of the miR-200c/141 cluster and that BMI1 inhibitors upregulate expression of miR-200c and miR-141. Our data suggest that BMI1 binds to the miR-200c/141 promoter and regulates it through transcription factor binding motifs E-box 2 and Z-box 1 to repress expression of miR-200c/141 cluster. We also show that PTC-209, a small molecule inhibitor of BMI1 gene expression induces cellular senescence and transcriptionally upregulates expression of miR-200c/141 cluster in breast cancer cells. Furthermore, inhibition of expression of miR-200c or miR-141 overcomes tumor suppressive effects of PTC-209 including induction of cellular senescence and downregulation of breast cancer stem cell phenotype. Therefore, our studies suggest a reciprocal regulation between BMI1 and miR-200c/141 cluster, and that BMI1 inhibitory drugs can further amplify their inhibitory effects on BMI1 via multiple mechanisms including posttranscriptional regulation by upregulating BMI1 targeting miRNAs.
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