PLK1 Inhibition Down-regulates Polycomb Group Protein BMI1 via Modulation of the miR-200c/141 Cluster

• Published in: The Journal of biological chemistry Vol. 290; no. 5; pp. 3033 - 3044
• Main Authors: Dimri, Manjari, Cho, Joon-Ho, Kang, Mingu, Dimri, Goberdhan P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.01.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Blotting, Western; Breast Cancer; Cancer Biology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Growth; Cell Line, Tumor; Cellular Regulation; Cellular Senescence; Female; Gene Regulation; Humans; microRNA (miRNA); MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Bases of Disease; Polo-Like Kinase 1; Polycomb; Polycomb Repressive Complex 1 - genetics; Polycomb Repressive Complex 1 - metabolism; Protein Binding; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Gene Regulation; microRNA (miRNA); Cellular Senescence; Cell Growth; Cellular Regulation; Polycomb; Cancer Biology; Breast Cancer
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.615179

The polycomb group protein BMI1 is an important regulator of cancer stem cell (CSC) phenotype and is often overexpressed in cancer cells. Its overexpression leads to increase in CSC fraction and therapy resistance in tumors. BMI1 functions via polycomb repressive complex 1 (PRC1)-mediated gene silencing and also via PRC1-independent transcriptional activities. At present, very little is known about the therapy reagents that can efficiently inhibit BMI1 expression, and the CSC phenotype. Here, we report that the polo-like kinase 1 (PLK1) regulates BMI1 expression, and that its inhibition can efficiently down-regulate BMI1 expression and PRC1 activity, and induce premature senescence in breast cancer cells. We also show that the exogenous BMI1 overexpression mitigates anti-oncogenic effects of PLK1 inhibition and overcomes senescence induction by PLK1 inhibitors. We further show that PLK1 inhibition down-regulates BMI1 by upregulating the miRNA-200c/141 cluster, which encodes miR-200c and miR-141, both of which are known to post-transcriptionally downregulate BMI1 expression. Thus, our data suggest that PLK1 inhibitors can be successfully used to inhibit growth of tumors in which PcG protein BMI1 is overexpressed or the PRC1 activity is deregulated. Background: BMI1 regulates cancer stem cell phenotype and is overexpressed in cancer cells. Results: PLK1 regulates BMI1 expression and its inhibitors suppress BMI1 expression, and induce premature senescence. Conclusion: BMI1 acts downstream of PLK1, and its expression is strongly inhibited by PLK1 inhibitor BI 2536. Significance: PLK1 inhibitors can be used to suppress growth of breast cancer cells overexpressing BMI1.