Bmi-1 Is a Crucial Regulator of Prostate Stem Cell Self-Renewal and Malignant Transformation

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, 90095, USA.
Cell stem cell (Impact Factor: 22.27). 12/2010; 7(6):682-93. DOI: 10.1016/j.stem.2010.11.013
Source: PubMed


The Polycomb group transcriptional repressor Bmi-1 is often upregulated in prostate cancer, but its functional roles in prostate stem cell maintenance and prostate cancer are unclear. Loss- and gain-of-function analysis in a prostate sphere assay indicates that Bmi-1 expression is required for self-renewal activity and maintenance of p63(+) stem cells. Loss of Bmi-1 blocks the self-renewal activity induced by heightened β-catenin signaling, suggesting that Bmi-1 is required for full activity of another self-renewal pathway. In vivo, Bmi-1 expression is necessary for normal prostate tubule regeneration. Altered self-renewal and proliferation through Bmi-1 modulation diminishes the susceptibility of prostate cells to transformation. In an in vivo prostate regeneration system, Bmi-1 inhibition protects prostate cells from FGF10-driven hyperplasia and slows the growth of aggressive Pten-deletion-induced prostate cancer. We conclude that Bmi-1 is a crucial regulator of self-renewal in adult prostate cells and plays important roles in prostate cancer initiation and progression.

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    • "To define the mechanism by which loss of PTEN diminishes ERb expression, we focused on BMI-1, the key regulatory component of the polycomb repressive complex-1 that modulates chromatin structure and represses the transcription of a number of genes (Cao et al., 2005; Jacobs et al., 1999; Miyazaki et al., 2008), for several reasons. BMI-1 has been implicated in prostate hyperplasia and tumorigenesis (Lukacs et al., 2010; van Leenders et al., 2007). We also found that expression of BMI-1 in ERb-expressing PTEN-depleted cells promoted tumor formation (Figure 2C). "
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    ABSTRACT: The role of ERβ in prostate cancer is unclear, although loss of ERβ is associated with aggressive disease. Given that mice deficient in ERβ do not develop prostate cancer, we hypothesized that ERβ loss occurs as a consequence of tumorigenesis caused by other oncogenic mechanisms and that its loss is necessary for tumorigenesis. In support of this hypothesis, we found that ERβ is targeted for repression in prostate cancer caused by PTEN deletion and that loss of ERβ is important for tumor formation. ERβ transcription is repressed by BMI-1, which is induced by PTEN deletion and important for prostate tumorigenesis. This finding provides a mechanism for how ERβ expression is regulated in prostate cancer. Repression of ERβ contributes to tumorigenesis because it enables HIF-1/VEGF signaling that sustains BMI-1 expression. These data reveal a positive feedback loop that is activated in response to PTEN loss and sustains BMI-1. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(12). DOI:10.1016/j.celrep.2015.02.063 · 8.36 Impact Factor
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    • "B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) is a specific marker of neural, hematopoietic, intestinal, and prostate stem cells89101112. Bmi1 is a polycomb-group gene whose product is a component of the polycomb repressive complex 1 (PRC1) and is thought to maintain the self-renewal capacity of stem cells91314. "
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    ABSTRACT: Asingle cells in undifferentiated spermatogonia are considered to be the most primitive forms of germ stem cells (GSCs). Although GFRα1 is thought to be a marker of Asingle cells, we found that Bmi1(High) is more specific than GFRα1 for Asingle cells. Bmi1(High) expression in Asingle cells is correlated with seminiferous stages, and its expression was followed by the proliferative stage of Asingle GSCs. In contrast, GFRα1 expression was seminiferous stage-independent. Fate analyses of EdU-positive Bmi1(High)-positive cell-derived Asingle cells revealed that these cells self-renewed or generated transient amplifying Apaired cells. Bmi1(High)-positive cells were resistant to irradiation-induced injury, after which they regenerated. Elimination of Bmi1(High)-positive cells from seminiferous tubules resulted in the appearance of tubules with seminiferous stage mismatches. Thus, in this study, we found that Bmi1(High) is a seminiferous stage-dependent marker for long-term GSCs and that Bmi1(High)-positive cells play important roles in maintaining GSCs and in regenerating spermatogenic progenitors after injury.
    Scientific Reports 08/2014; 4:6175. DOI:10.1038/srep06175 · 5.58 Impact Factor
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    • "It has been reported that Bmi1 represses Survivin expression in neurospheres by increased H3K27me3 through directly binding to the Survivin promoter [104]. In prostate cancer, Bmi1 is often upregulated and binds to the Slit2 promoter, which is consistent with the hypermethylation of the Slit2 promoter and thereby represses its expression [107] [113]. All of these results suggest that the high expression of Bmi1 may enhance the methylation of the Slit2 promoter and thereby reduce Slit2 expression. "
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    ABSTRACT: Glioblastoma multiforme (GBM) is by far the most common and most aggressive malignant primary tumor in humans and has poor outcomes despite many advances in treatment using combinations of surgery, radiotherapy and chemotherapy. Recent studies demonstrate that GBM contains a subpopulation of cancer cells with stem cell characteristics, including self-renewal and multipotentiality, and that these cancer stem cells contribute to disease progression. MicroRNAs (miRNAs) are small non-coding regulatory RNA molecules that regulate a variety of cellular processes, including stem cell maintenance. An accumulating body of evidence shows that miR-218 may act as a tumor suppressor by inhibiting glioblastoma invasion, migration, proliferation and stemness through its different targets, indicating the great potential and relevance of miR-218 as a novel class of therapeutic target in glioblastoma.
    Cancer Letters 07/2014; 353(1). DOI:10.1016/j.canlet.2014.07.011 · 5.62 Impact Factor
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