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.
Highlights
BMI1 regulates cancer stem cell phenotype and is overexpressed in cancer cells
We determined whether polo-like kinase 1 (PLK1) knockdown results in down-regulation of H2AK119 ubiquitination activity of polycomb repressive complex 1 (PRC1) by analyzing total H2A and H2AK119Ub levels by Western blot analysis
Our data indicated that PLK1 knockdown using two different shRNAs (PLKi46 and PLKi47) but not a control shRNA resulted in down-regulation of BMI1 as well as decreased levels of H2AK119Ub in MCF7, MDA-MB-231, and MDA-MB-468 cells (Fig. 1A)
Summary
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. The polycomb group protein BMI1 is an important regulator of cancer stem cell (CSC) phenotype and is often overexpressed in cancer cells. 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. 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. The miR-200c has been shown to regulate breast cancer stem cell phenotype by targeting PcG protein BMI1 [10]. Other miRNAs such as miR-15a, miR-16, miR-218, and miR-128 have been shown to regulate expression of BMI1 and cancer stem cell phenotype to a varying degree in different cancer cell types [30,31,32]. PLK1 inhibition appears to regulate BMI1 expression via up-regulation of miR200c and miR-141
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