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Cyclin E1 Is a Common Target of BMI1 and MYCN and a Prognostic Marker for Neuroblastoma Progression

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Cyclin E1 Is a Common Target of BMI1 and MYCN and a Prognostic Marker for Neuroblastoma Progression Oncogene (2012) 31, 3785–3795 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc ORIGINAL ARTICLE Cyclin E1 is a common target of BMI1 and MYCN and a prognostic marker for neuroblastoma progression L Mao1,2,6, J Ding1,6, A Perdue1, L Yang1, Y Zha1,3, M Ren1, S Huang4, H Cui5 and H-F Ding1 1Cancer Center and Department of Pathology, Cancer Center, Georgia Health Sciences University, Augusta, GA, USA; 2Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 3Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China; 4Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA, USA and 5The State Key Laboratory of Silkworm Functional Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing, China The Polycomb transcription repressor BMI1 is highly 1991). It is a component of the Polycomb repressive expressed in human neuroblastomas and is required for complex 1 required for transcriptional repression of the clonogenic self-renewal and tumorigenicity of human genes important in development and differentiation neuroblastoma cell lines. The molecular basis of BMI1 (Valk-Lingbeek et al., 2004; Schwartz and Pirrotta, action in neuroblastoma cells is not well understood. Here 2007; Sauvageau and Sauvageau, 2010). BMI1 has we report that BMI1 has a critical role in stabilizing diverse biological functions as demonstrated by pheno- cyclin E1 by repressing the expression of FBXW7, a typic analysis of Bmi1À/À mice. These mice display substrate-recognition subunit of the SCF E3 ubiquitin defects in axial skeleton patterning, hematopoiesis and ligase that targets cyclin E1 for degradation. BMI1 binds neural development (van der Lugt et al., 1994). Later to the FBXW7 locus in vivo and represses its mRNA studies have revealed a critical role of BMI1 in the self- expression. Overexpression of cyclin E1 or abrogation of renewal of normal and cancer stem cells (Lessard and FBXW7 induction rescues the cell-death phenotype of Sauvageau, 2003; Molofsky et al., 2003; Park et al., BMI1 knockdown. Moreover, MYCN, an oncoprotein in 2003; Iwama et al., 2004). the pathogenesis of high-risk neuroblastomas, is able to A key downstream target of BMI1 is the Ink4a-ARF counteract the death-inducing effect of BMI1 knockdown locus that encodes two tumor suppressors, p16Ink4a and by activating CCNE1 transcription. We further show that p14ARF (p19ARF in the mouse; Jacobs et al., 1999a; Park high cyclin E1 expression is associated with Stage 4 et al., 2004). p16Ink4a inhibits the cyclin D-CDK4/6 neuroblastomas and poor prognosis in patients. These kinase responsible for phosphorylation of pRb during findings suggest a molecular mechanism for the oncogenic the cell cycle. The resulting hypophosphorylated pRb activity of BMI1 and MYCN in neuroblastoma pathogen- binds E2F and represses its transcriptional activation of esis and progression by maintaining cyclin E1 levels. the genes that promote S-phase entry, leading to cell Oncogene (2012) 31, 3785–3795; doi:10.1038/onc.2011.536; cycle arrest and senescence. p14ARF inhibits MDM2, published online 28 November 2011 which targets p53 for ubiquitin-dependent degradation, leading to accumulation of p53 and transcriptional Keywords: BMI1; cyclin E1; FBXW7, MYCN; neuro- activation of its target genes that promote cell cycle blastoma arrest, senescence and apoptosis (Lowe and Sherr, 2003). Importantly, inactivation of the Ink4a-ARF locus or individual p16Ink4a and p19ARF partially rescues the self-renewal and frequency of stem cells in the central Introduction and peripheral nervous systems in Bmi1À/À mice (Molofsky et al., 2003, 2005; Bruggeman et al., 2005), BMI1 is a member of the Polycomb group family of demonstrating that repression of the Ink4a-ARF locus is transcriptional repressors that was originally identified critical for Bmi1 to maintain stem cells. However, the as an oncogenic partner of c-Myc in murine lympho- partial rescue of Bmi1À/À phenotype by ablation of magenesis (Haupt et al., 1991; van Lohuizen et al., p16Ink4a and p19ARF also suggests the involvement of addi- tional target genes for the biological functions of BMI1. Correspondence: Dr H Cui, The State Key Laboratory of Silkworm BMI1 is highly expressed in human neuroblastomas Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, 2 Tianshenqiao, Chongqing 400716, China. and neuroblastoma cell lines (Cui et al., 2006, 2007; E-mail: [email protected] or Dr H-F Ding, Cancer Center and Nowak et al., 2006; Ochiai et al., 2010). Neuroblastoma Department of Pathology, Cancer Center, CN-4132, Georgia Health is a common childhood malignant tumor of the Sciences University, 1120 15th Street, Augusta, GA 30912, USA. sympathetic nervous system that arises in paravertebral E-mail: [email protected] or sympathetic ganglia and the adrenal medulla (Brodeur, 6These authors contributed equally to this work. Received 22 August 2011; revised 7 October 2011; accepted 9 October 2003). Both tissues originate from neural crest cells, a 2011; published online 28 November 2011 transient, highly migratory population of multipotent Maintenance of cyclin E1 by BMI1 and MYCN L Mao et al 3786 stem cells that require BMI1 for their self-renewal their proliferation in culture (Figures 1a and b), but (Molofsky et al., 2003, 2005). We have recently significantly reduced their ability to grow in soft agar, as demonstrated an essential role of BMI1 in the main- judged by both the number and size of colonies tenance of the clonogenic self-renewal and tumorigeni- (Figure 1c). By contrast, cells of the remaining 6 clones city of human neuroblastoma cell lines (Cui et al., 2006, (numbers 2, 9, 11, 15, 20 and 22) were extremely 2007). Moreover, we have shown that Bmi1 cooperates sensitive to BMI1 knockdown (referred to below as with MYCN in transformation of avian neural crest BMI1-sensitive clones), showing a marked decrease in cells by inhibiting the pro-apoptotic activity of MYCN clonogenicity (Figures 1d–e). Following BMI1 knock- (Cui et al., 2007). Amplification of the oncogene down, these cells progressively rounded up and detached MYCN, which occurs in B22% of neuroblastoma from the culture matrix (Figures 1f–g). The cell death cases, is strongly associated with highly malignant phenotype induced by the BMI1sh-48576 sequence, behavior and poor prognosis (Maris and Matthay, which targets the 30-untranslated region of human 1999; Brodeur, 2003; Schwab, 2004). BMI1 mRNA (Supplementary Figure 2a), could be In this report, we present evidence for cyclin E1 as a effectively rescued by retroviral expression of the BMI1 common downstream target of BMI1 and MYCN in coding sequence (Supplementary Figures 2b and c), promoting the survival of neuroblastoma cells. MYCN demonstrating that the effect is a result of BMI1 transcriptionally activates the expression of cyclin E1, silencing. Together, these findings reveal differential whereas BMI1 represses the transcription of FBXW7 to sensitivities of individual BE(2)-C cells to the reduction block cyclin E1 degradation. These findings provide a in BMI1 levels. molecular mechanism for maintaining high cyclin E1 expression, which is associated with poor outcome and disease progression in neuroblastoma patients. BMI1 knockdown induces non-apoptotic cell death independently of p16Ink4a and p14ARF We next focused our investigation on the cell death- Results inducing effect of BMI1 knockdown. It has been shown previously that BMI1 can promote cell survival by Individual neuroblastoma cells display differential suppressing apoptosis (Jacobs et al., 1999b; Yamashita sensitivities to BMI1 knockdown et al., 2008). However, the majority of the dying cells To investigate the molecular basis of BMI1 action in following BMI1 knockdown displayed no morphologic neuroblastoma cells, we used an RNAi-based approach features of apoptosis, such as cell shrinkage and for knockdown of BMI1 expression in BE(2)-C cells, a membrane blebbing (Figure 1f). Propidium iodide flow human neuroblastoma cell line enriched for cells capable cytometry analysis of BMI1-sensitive clone-2 and -9 cells of clonogenic self-renewal in a BMI1-dependent manner following BMI1 knockdown revealed no significant (Cui et al., 2006). We tested four retroviral constructs numbers of cells with sub-G1 DNA content (Supple- expressing shRNA sequences against different regions of mentary Figure 3a), a characteristic of apoptotic cells the human BMI1 gene, and two of them (BMI1sh-48576 (Riccardi and Nicoletti, 2006). We also observed no and-48580) were highly effective in knockdown of BMI1 significant levels of membrane annexin V staining during expression (Supplementary Figure 1a) and had a similar BMI1 knockdown-induced cell death (Supplementary inhibitory effect on tumor cell clonogenicity (Supple- Figure 3b). Annexin V binds externalized phosphati- mentary Figure 1b). These findings confirmed our dylserine on the plasma membrane, an early event in previous observation of a critical role of BMI1 in apoptosis (Martin et al., 1995). Finally, treatment of maintaining the clonogenicity of neuroblastoma cells clone-2 and -9 cells with the cell permeable pan-caspase (Cui et al., 2006, 2007) and demonstrated the functional inhibitor zVAD-FMK failed to prevent BMI1 knock- specificity of these BMI1 shRNA sequences. down-induced
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