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: 22.15). 12/2010; 7(6):682-93. DOI: 10.1016/j.stem.2010.11.013
Source: PubMed

ABSTRACT 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.

  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Abbreviations: AdSC adult stem cell, CSC cancer stem cell, EnProgC endothelial progenitor cell, ESC embryonic stem cell, HProgC hematopoietic progenitor cell, HSC hematopoietic stem cell, ProgC progenitor cell, PSC pluripotent stem cell, iPSC induced pluripotent stem cell. References: 1, Ginestier et al. 2007; 2, Sangiorgi and Capecchi 2008; 3, Lukacs et al. 2010; 4, Pontier and Muller 2009; 5, Taddei et al. 2008; 6, Krause et al. 1996; 7, Furness et al. 2006; 8, Tardio 2009; 9, Annaloro et al. 2011; 10, Srour et al. 1991; 11, Basso and Timeus 1998; 12, Günthert et al. 1991; 13, Zöller 2011; 14, Singh et al. 2001; 15, Takaishi et al. 2009; 16, Zhang et al. 2008; 17, Augello et al. 2010; 18, Salcido et al. 2010; 19, Ponnusamy and Batra 2008; 20, Liu et al. 2006; 21, Mizrak et al. 2008; 22, Ricci-Vitani et al. 2007; 23, Kemper et al. 2010; 24, O'Brien et al. 2007; 25, Bunting 2002; 26, Monzani et al. 2007; 27, Krupkova et al. 2010; 28, Dell'Albani 2008; 29, Monk and Holding 2001; 30, Carpenter et al. 2003. TF does not exist as a separate entity, but as part of a larger carbohydrate structure (O-glycan core-1) carried by many glycoproteins primarily of the mucin-type. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the cancer stem cell concept has been widely accepted, several strategies have been proposed to attack cancer stem cells (CSC). Accordingly, stem cell markers are now preferred therapeutic targets. However, the problem of tumor specificity has not disappeared but shifted to another question: how can cancer stem cells be distinguished from normal stem cells, or more specifically, how do CSC markers differ from normal stem cell markers? A hypothesis is proposed which might help to solve this problem in at least a subgroup of stem cell markers. Glycosylation may provide the key.
    SpringerPlus 12/2013; 2(1):301. DOI:10.1186/2193-1801-2-301
  • Source
    • "In vitro, cells was infected with lentiviral particles of the LV‐STI‐1‐ shRNA (sc‐153893‐V, Santa Cruz), LV‐HIF‐1a‐shRNA (sc‐35562‐V, Santa Cruz) or scramble LV‐control‐shRNA (sc‐108080‐V, Santa Cruz) under manufacture's instruction (Lukacs et al, 2010). For shRNA experiments in vivo, experimental animals were stereotaxically injected with LV‐STI‐1‐shRNA or scramble LV‐control‐shRNA in accordance with the coordinates as above mentioned. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stress-inducible protein-1 (STI-1) is the proposed ligand for the cellular prion protein (PrPC), which is thought to facilitate recovery following stroke. Whether STI-1 expression is affected by stroke and how its signalling facilitates recovery remain elusive. Brain slices from patients that died of ischemic stroke were collected for STI-1 immunohistochemistry. These findings were compared to results from cell cultures, mice with or without the PrPC knockout, and rats. Based on these findings, molecular and pharmacological interventions were administered to investigate the underlying mechanisms and to test the possibility for therapy in experimental stroke models. STI-1 was upregulated in the ischemic brains from humans and rodents. The increase in STI-1 expression in vivo was not cell-type specific, as it was found in neurons, glia and endothelial cells. Likewise, this increase in STI-1 expression can be mimicked by sublethal hypoxia in primary cortical cultures (PCCs) in vitro, and appear to have resulted from the direct binding of the hypoxia inducible factor-1α (HIF-1α) to the STI-1 promoter. Importantly, this STI-1 signalling promoted bone marrow derived cells (BMDCs) proliferation and migration in vitro and recruitment to the ischemic brain in vivo, and augmenting its signalling facilitated neurological recovery in part by recruiting BMDCs to the ischemic brain. Our results thus identified a novel mechanism by which ischemic insults can trigger a self-protective mechanism to facilitate recovery. This work identifies HIF-1α-mediated transcription of STI-1 and PrPc interaction as leading to BMDCs recruitment into ischemic brains following stroke in both patients and animal models of stroke, highlighting novel neuroprotective possibilities.
    EMBO Molecular Medicine 08/2013; 5(8). DOI:10.1002/emmm.201202258 · 8.25 Impact Factor
Show more


Available from