title: PLK1 inhibition down-regulates polycomb group protein BMI1 via modulation of the miR-200c/141 cluster.
abstract: 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.
authors.affiliation: From the Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University Medical Center, Washington, DC 20037 gdimri@gwu.edu.
authors.forename: Manjari
authors.initials: M
authors.lastname: Dimri
authors.affiliation: From the Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University Medical Center, Washington, DC 20037.
authors.forename: Joon-Ho
authors.initials: JH
authors.lastname: Cho
authors.affiliation: From the Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University Medical Center, Washington, DC 20037.
authors.forename: Mingu
authors.initials: M
authors.lastname: Kang
authors.affiliation: From the Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University Medical Center, Washington, DC 20037 mdimri@gwu.edu.
authors.forename: Goberdhan P
authors.initials: GP
authors.lastname: Dimri
mesh_terms: D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D035683:MicroRNAs; D063150:Polycomb Repressive Complex 1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C069077:BMI1 protein, human; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human
keywords: Breast Cancer; Cancer Biology; Cell Growth; Cellular Regulation; Cellular Senescence; Gene Regulation; Polycomb; microRNA (miRNA)