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Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Oncogene volume 31, pages 187–199 (2012)Cite this article

Abstract

Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathway-driven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell–cell interaction between the CD133+ Hh receptor cells and the CD133− Hh-secreting cells.

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References

  • Annabi B, Doumit J, Plouffe K, Laflamme C, Lord-Dufour S, Beliveau R . (2010). Members of the low-density lipoprotein receptor-related proteins provide a differential molecular signature between parental and CD133+ DAOY medulloblastoma cells. Mol Carcinog 49: 710–717.

    CAS  PubMed  Google Scholar 

  • Annabi B, Rojas-Sutterlin S, Laflamme C, Lachambre MP, Rolland Y, Sartelet H et al. (2008). Tumor environment dictates medulloblastoma cancer stem cell expression and invasive phenotype. Mol Cancer Res 6: 907–916.

    Article  CAS  PubMed  Google Scholar 

  • Ayrault O, Zhao H, Zindy F, Qu C, Sherr CJ, Roussel MF . (2010). Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells. Cancer Res 70: 5618–5627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444: 756–760.

    Article  CAS  PubMed  Google Scholar 

  • Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, Werbowetski-Ogilvie T et al. (2007). IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448: 1015–1021.

    Article  CAS  PubMed  Google Scholar 

  • Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN et al. (2002). Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297: 1559–1561.

    Article  CAS  PubMed  Google Scholar 

  • Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E . (2004). Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118: 635–648.

    Article  CAS  PubMed  Google Scholar 

  • Blazek ER, Foutch JL, Maki G . (2007). Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133− cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67: 1–5.

    Article  CAS  PubMed  Google Scholar 

  • Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K . (2006). Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 20: 1123–1136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruggeman SW, Hulsman D, Tanger E, Buckle T, Blom M, Zevenhoven J et al. (2007). Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12: 328–341.

    Article  CAS  PubMed  Google Scholar 

  • Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM et al. (2010). A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17: 362–375.

    Article  CAS  PubMed  Google Scholar 

  • Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A . (2007). HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17: 165–172.

    Article  CAS  PubMed  Google Scholar 

  • Crawford JR, MacDonald TJ, Packer RJ . (2007). Medulloblastoma in childhood: new biological advances. Lancet Neurol 6: 1073–1085.

    Article  CAS  PubMed  Google Scholar 

  • Dahl JA, Collas P . (2008). A rapid micro chromatin immunoprecipitation assay (microChIP). Nat Protoc 3: 1032–1045.

    Article  CAS  PubMed  Google Scholar 

  • Dahmane N, Ruiz i Altaba A . (1999). Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126: 3089–3100.

    PubMed  Google Scholar 

  • Dahmane N, Sanchez P, Gitton Y, Palma V, Sun T, Beyna M et al. (2001). The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 128: 5201–5212.

    CAS  PubMed  Google Scholar 

  • Ellison DW . (2010). Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease. Acta Neuropathol 120: 305–316.

    Article  PubMed  Google Scholar 

  • Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE et al. (2005). beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol 23: 7951–7957.

    Article  CAS  PubMed  Google Scholar 

  • Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM et al. (2006). Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66: 7445–7452.

    Article  CAS  PubMed  Google Scholar 

  • Fattet S, Haberler C, Legoix P, Varlet P, Lellouch-Tubiana A, Lair S et al. (2009). Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics. J Pathol 218: 86–94.

    Article  CAS  PubMed  Google Scholar 

  • Flora A, Klisch TJ, Schuster G, Zoghbi HY . (2009). Deletion of Atoh1 disrupts Sonic Hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science 326: 1424–1427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fuccillo M, Joyner AL, Fishell G . (2006). Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat Rev Neurosci 7: 772–783.

    Article  CAS  PubMed  Google Scholar 

  • Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C et al. (2010). Subtypes of medulloblastoma have distinct developmental origins. Nature 468: 1095–1099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilbertson RJ . (2004). Medulloblastoma: signalling a change in treatment. Lancet Oncol 5: 209–218.

    Article  PubMed  Google Scholar 

  • Gilbertson RJ, Ellison DW . (2008). The origins of medulloblastoma subtypes. Annu Rev Pathol 3: 341–365.

    Article  CAS  PubMed  Google Scholar 

  • Glinsky GV, Berezovska O, Glinskii AB . (2005). Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest 115: 1503–1521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA et al. (2004). The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64: 7794–7800.

    Article  CAS  PubMed  Google Scholar 

  • Huse JT, Holland EC . (2010). Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer 10: 319–331.

    Article  CAS  PubMed  Google Scholar 

  • Johnson R, Wright KD, Gilbertson RJ . (2009). Molecular profiling of pediatric brain tumors: insight into biology and treatment. Curr Oncol Rep 11: 68–72.

    Article  CAS  PubMed  Google Scholar 

  • Kimura H, Stephen D, Joyner A, Curran T . (2005). Gli1 is important for medulloblastoma formation in Ptc1+/− mice. Oncogene 24: 4026–4036.

    Article  CAS  PubMed  Google Scholar 

  • Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P et al. (2008). Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3: e3088.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee A, Kessler JD, Read TA, Kaiser C, Corbeil D, Huttner WB et al. (2005). Isolation of neural stem cells from the postnatal cerebellum. Nat Neurosci 8: 723–729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee EY, Ji H, Ouyang Z, Zhou B, Ma W, Vokes SA et al. (2010). Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis. Proc Natl Acad Sci USA 107: 9736–9741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani P et al. (2004). Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428: 337–341.

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW et al. (2006). Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66: 6063–6071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D et al. (2006). A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res 66: 10171–10178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCord AM, Jamal M, Williams ES, Camphausen K, Tofilon PJ . (2009). CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin Cancer Res 15: 5145–5153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michael LE, Westerman BA, Ermilov AN, Wang A, Ferris J, Liu J et al. (2008). Bmi1 is required for Hedgehog pathway-driven medulloblastoma expansion. Neoplasia 10: 1343–1349, 5p following 1349.

    Article  PubMed  PubMed Central  Google Scholar 

  • Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S et al. (2010). Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29: 1408–1414.

    Article  PubMed  PubMed Central  Google Scholar 

  • Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM et al. (2003). Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci USA 100: 7331–7336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oliver TG, Read TA, Kessler JD, Mehmeti A, Wells JF, Huynh TT et al. (2005). Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development 132: 2425–2439.

    Article  CAS  PubMed  Google Scholar 

  • Pallini R, Ricci-Vitiani L, Montano N, Mollinari C, Biffoni M, Cenci T et al. (2010). Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer 117: 162–174.

    Article  PubMed  Google Scholar 

  • Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC et al. (2010). The genetic landscape of the childhood cancer medulloblastoma. Science 331: 435–439.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pistollato F, Rampazzo E, Persano L, Abbadi S, Frasson C, Denaro L et al. (2010). Interaction of hypoxia-inducible factor-1alpha and Notch signaling regulates medulloblastoma precursor proliferation and fate. Stem Cells 28: 1918–1929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME et al. (2002). Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415: 436–442.

    Article  CAS  PubMed  Google Scholar 

  • Rao G, Pedone CA, Del Valle L, Reiss K, Holland EC, Fults DW . (2004). Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23: 6156–6162.

    Article  CAS  PubMed  Google Scholar 

  • Read TA, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW et al. (2009). Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15: 135–147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Romer JT, Kimura H, Magdaleno S, Sasai K, Fuller C, Baines H et al. (2004). Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−7sol;−) mice. Cancer Cell 6: 229–240.

    Article  CAS  PubMed  Google Scholar 

  • Ruiz i Altaba A, Palma V, Dahmane N . (2002). Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci 3: 24–33.

    Article  CAS  PubMed  Google Scholar 

  • Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG et al. (2008). Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14: 123–134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res 63: 5821–5828.

    CAS  PubMed  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. (2004). Identification of human brain tumour initiating cells. Nature 432: 396–401.

    Article  CAS  PubMed  Google Scholar 

  • Subkhankulova T, Zhang X, Leung C, Marino S . (2010). Bmi1 directly represses p21Waf1/Cip1 in Shh-induced proliferation of cerebellar granule cell progenitors. Mol Cell Neurosci 45: 151–162.

    Article  CAS  PubMed  Google Scholar 

  • Sutter R, Shakhova O, Bhagat H, Behesti H, Sutter C, Penkar S et al. (2010). Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas. Oncogene 29: 1845–1856.

    Article  CAS  PubMed  Google Scholar 

  • Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X et al. (2002). Mutations in SUFU predispose to medulloblastoma. Nat Genet 31: 306–310.

    Article  CAS  PubMed  Google Scholar 

  • Thomas WD, Chen J, Gao YR, Cheung B, Koach J, Sekyere E et al. (2009). Patched1 deletion increases N-Myc protein stability as a mechanism of medulloblastoma initiation and progression. Oncogene 28: 1605–1615.

    Article  CAS  PubMed  Google Scholar 

  • Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC et al. (2006). Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24: 1924–1931.

    Article  CAS  PubMed  Google Scholar 

  • Thon N, Damianoff K, Hegermann J, Grau S, Krebs B, Schnell O et al. (2008). Presence of pluripotent CD133(+) cells correlates with malignancy of gliomas. Mol Cell Neurosci 43: 51–59.

    Article  PubMed  Google Scholar 

  • Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV et al. (2000). Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97: 14720–14725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M . (2004). Stem cells and cancer; the polycomb connection. Cell 118: 409–418.

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A et al. (2010). Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468: 829–833.

    Article  CAS  PubMed  Google Scholar 

  • Wechsler-Reya RJ, Scott MP . (1999). Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22: 103–114.

    Article  CAS  PubMed  Google Scholar 

  • Wiederschain D, Chen L, Johnson B, Bettano K, Jackson D, Taraszka J et al. (2007). Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis. Mol Cell Biol 27: 4968–4979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan X, Ma L, Yi D, Yoon JG, Diercks A, Foltz G et al. (2011). A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations. Proc Natl Acad Sci USA 108: 1591–1596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH et al. (2010). Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 12: 982–992.

    Article  PubMed  Google Scholar 

  • Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M et al. (2008). Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14: 135–145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG et al. (1997). AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90: 5002–5012.

    CAS  PubMed  Google Scholar 

  • Yu CC, Chiou GY, Lee YY, Chang YL, Huang PI, Cheng YW et al. (2010). Medulloblastoma-derived tumor stem-like cells acquired resistance to TRAIL-induced apoptosis and radiosensitivity. Childs Nerv Syst 26: 897–904.

    Article  PubMed  Google Scholar 

  • Zakrzewska M, Zakrzewski K, Gresner SM, Piaskowski S, Zalewska-Szewczyk B, Liberski PP . (2011). Polycomb genes expression as a predictor of poor clinical outcome in children with medulloblastoma. Childs Nerv Syst 27: 79–86.

    Article  PubMed  Google Scholar 

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Acknowledgements

We are very grateful to Atsushi Iwama for kind provision of Bmi1 shRNA lentiviral construct. We thank Merry Wang for artistic illustrations. This work was supported by funds from the Department of Surgery at McMaster University, the Ontario Institute for Cancer Research (OICR) and the JP Bickell Foundation. XW held a training award from the Stem Cell Network.

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Authors and Affiliations

  1. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada

    X Wang, C Venugopal, B Manoranjan, N McFarlane, E O'Farrell, S Nolte & S K Singh

  2. Department of Surgery, McMaster University, Hamilton, Ontario, Canada

    T Gunnarsson, R Hollenberg & S K Singh

  3. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    J Kwiecien

  4. Arthur and Sonia Labatt Brain Tumor Research Centre and Department of Surgery, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

    P Northcott & M D Taylor

  5. Arthur and Sonia Labatt Brain Tumor Research Centre and Department of Pediatric Laboratory Medicine, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

    C Hawkins

  6. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    S K Singh

  7. Department of Neuroscience, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada

    S K Singh

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  1. X Wang
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Correspondence to S K Singh.

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Wang, X., Venugopal, C., Manoranjan, B. et al. Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells. Oncogene 31, 187–199 (2012). https://doi.org/10.1038/onc.2011.232

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