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	Manjari Dimri, Joon-Ho Cho, Mingu Kang, Goberdhan P Dimri
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 5 Pg. 3033-44 (Jan 30 2015) ISSN: 1083-351X [Electronic] United States
PMID	25505268 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright	© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References	BMI1 protein, human Cell Cycle Proteins MIRN141 microRNA, human MIRN200 microRNA, human MicroRNAs Proto-Oncogene Proteins Polycomb Repressive Complex 1 Protein Serine-Threonine Kinases
Topics	Blotting, Western Cell Cycle Proteins (genetics, metabolism) Cell Line, Tumor Female Humans MicroRNAs (genetics, metabolism) Polycomb Repressive Complex 1 (genetics, metabolism) Protein Binding Protein Serine-Threonine Kinases (genetics, metabolism) Proto-Oncogene Proteins (genetics, metabolism) Reverse Transcriptase Polymerase Chain Reaction Polo-Like Kinase 1

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