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  • Review Article
  • Published:

Polycomb silencers control cell fate, development and cancer

Key Points

  • Epigenetic gene silencing is an important mechanism for the loss of gene function and collaborates with genetic mutation in the initiation and progression of human cancer.

  • Polycomb group (PcG) proteins regulate epigenetically mediated transcriptional silencing. They are involved in the maintenance of embryonic and adult stem cells and have been implicated in cancer development.

  • PcG-mediated repression of key tumour-suppressor pathways, as well as their role in the regulation of stem cell maintenance might contribute to their oncogenic function.

  • The recent global identification of PcG target genes provides the first insights into the mechanisms that govern stem cell maintenance and imply a dynamic regulation of PcG function during differentiation.

Abstract

Polycomb group (PcG) proteins are epigenetic gene silencers that are implicated in neoplastic development. Their oncogenic function might be associated with their well-established role in the maintenance of embryonic and adult stem cells. In this review, we discuss new insights into the possible mechanisms by which PcGs regulate cellular identity, and speculate how these functions might be relevant during tumorigenesis.

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Figure 1: Polycomb proteins function as repressors of Hox genes.
Figure 2: Epigenetic gene silencing by Polycomb protein complexes.
Figure 3: Potential functions of Polycomb proteins during tumour development.
Figure 4: Polycomb-mediated gene expression changes during differentiation.

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References

  1. Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nature Rev. Genet. 3, 415–428 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Martinez, A. M. & Cavalli, G. The role of Polycomb group proteins in cell cycle regulation during development. Cell Cycle 5, 1189–1197 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Valk-Lingbeek, M. E., Bruggeman, S. W. & van Lohuizen, M. Stem cells and cancer; the Polycomb connection. Cell 118, 409–418 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Gil, J., Bernard, D. & Peters, G. Role of Polycomb group proteins in stem cell self-renewal and cancer. DNA Cell Biol. 24, 117–125 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Akasaka, T. et al. A role for mel-18, a Polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton. Development 122, 1513–1522 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Core, N. et al. Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development 124, 721–729 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. del Mar Lorente, M. et al. Loss- and gain-of-function mutations show a Polycomb group function for Ring1A in mice. Development 127, 5093–5100 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. van der Lugt, N. M. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–769 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Levine, S. S., King, I. F. & Kingston, R. E. Division of labor in Polycomb group repression. Trends Biochem. Sci. 29, 478–485 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Lund, A. H. & van Lohuizen, M. Polycomb complexes and silencing mechanisms. Curr. Opin. Cell Biol. 16, 239–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Czermin, B. et al. Drosophila Enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Muller, J. et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197–208 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Fischle, W. et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 17, 1870–1881 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Min, J., Zhang, Y. & Xu, R. M. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev. 17, 1823–1828 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Francis, N. J., Kingston, R. E. & Woodcock, C. L. Chromatin compaction by a Polycomb group protein complex. Science 306, 1574–1577 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Papp, B. & Muller, J. Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. Genes Dev. 20, 2041–2054 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schwartz, Y. B. et al. Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nature Genet. 38, 700–705 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Klymenko, T. et al. A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities. Genes Dev. 20, 1110–1122 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grimaud, C. et al. RNAi components are required for nuclear clustering of Polycomb group response elements. Cell 124, 957–971 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Otte, A. P. & Kwaks, T. H. Gene repression by Polycomb group protein complexes: a distinct complex for every occasion? Curr. Opin. Genet. Dev. 13, 448–454 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Dellino, G. I. et al. Polycomb silencing blocks transcription initiation. Mol. Cell 13, 887–893 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Francis, N. J. & Kingston, R. E. Mechanisms of transcriptional memory. Nature Rev. Mol. Cell Biol. 2, 409–421 (2001).

    Article  CAS  Google Scholar 

  26. Wang, L. et al. Hierarchical recruitment of Polycomb group silencing complexes. Mol. Cell 14, 637–646 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Cao, R., Tsukada, Y. & Zhang, Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol. Cell 20, 845–854 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Kuzmichev, A., Jenuwein, T., Tempst, P. & Reinberg, D. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol. Cell 14, 183–193 (2004). Data are presented to indicate that the substrate specificity of distinct 'PRC2-like' complexes is determined by association with different EED isoforms.

    Article  CAS  PubMed  Google Scholar 

  29. Daujat, S., Zeissler, U., Waldmann, T., Happel, N. & Schneider, R. HP1 binds specifically to Lys26-methylated histone H1.4, whereas simultaneous Ser27 phosphorylation blocks HP1 binding. J. Biol. Chem. 280, 38090–38095 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Vire, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871–874 (2006). The first demonstration of a direct link between PcG-mediated gene repression and DNA methylation, two key mechanisms of epigenetic silencing.

    Article  CAS  PubMed  Google Scholar 

  31. Haupt, Y., Alexander, W. S., Barri, G., Klinken, S. P. & Adams, J. M. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 65, 753–763 (1991).

    Article  CAS  PubMed  Google Scholar 

  32. van Lohuizen, M. et al. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 65, 737–752 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678–2690 (1999). References 33 and 34 identify the Cdkn2a locus as a crucial target of BMI1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sherr, C. J. The INK4a/ARF network in tumour suppression. Nature Rev. Mol. Cell Biol. 2, 731–737 (2001).

    Article  CAS  Google Scholar 

  36. Lowe, S. W. & Sherr, C. J. Tumor suppression by Ink4a–Arf: progress and puzzles. Curr. Opin. Genet. Dev. 13, 77–83 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Gil, J., Bernard, D., Martinez, D. & Beach, D. Polycomb CBX7 has a unifying role in cellular lifespan. Nature Cell Biol. 6, 67–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Voncken, J. W. et al. RNF2 (RING1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc. Natl Acad. Sci. USA 100, 2468–2473 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lessard, J. et al. Functional antagonism of the Polycomb-group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev. 13, 2691–2703 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ohta, H. et al. Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells. J. Exp. Med. 195, 759–770 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kirmizis, A., Bartley, S. M. & Farnham, P. J. Identification of the Polycomb group protein SU(Z)12 as a potential molecular target for human cancer therapy. Mol. Cancer Ther. 2, 113–121 (2003).

    CAS  PubMed  Google Scholar 

  42. van Kemenade, F. J. et al. Coexpression of BMI-1 and EZH2 Polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. Blood 97, 3896–3901 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Raaphorst, F. M. et al. Coexpression of BMI-1 and EZH2 Polycomb group genes in Reed–Sternberg cells of Hodgkin's disease. Am. J. Pathol. 157, 709–715 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Visser, H. P. et al. The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br. J. Haematol. 112, 950–958 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Bracken, A. P. et al. EZH2 is downstream of the pRB–E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Varambally, S. et al. The Polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Su, I. H. et al. Polycomb group protein EZH2 controls actin polymerization and cell signaling. Cell 121, 425–436 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Squazzo, S. L. et al. Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res. 16, 890–900 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kuzmichev, A. et al. Composition and histone substrates of Polycomb repressive group complexes change during cellular differentiation. Proc. Natl Acad. Sci. USA 102, 1859–1864 (2005). Based on data obtained in a mouse model for prostate cancer, the authors speculate that changes in PcG complex composition reset gene expression patterns, thereby promoting tumour progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Lee, T. I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006). References 49, 52 and 53 globally map PcG binding sites in mammalian embryonic cell lines and analyse changes at PcG target genes during differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pardal, R., Clarke, M. F. & Morrison, S. J. Applying the principles of stem-cell biology to cancer. Nature Rev. Cancer 3, 895–902 (2003).

    Article  CAS  Google Scholar 

  55. Meshorer, E. & Misteli, T. Chromatin in pluripotent embryonic stem cells and differentiation. Nature Rev. Mol. Cell Biol. 7, 540–546 (2006).

    Article  CAS  Google Scholar 

  56. Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nature Cell Biol. 8, 532–538 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. O'Carroll, D. et al. The Polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330–4336 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Shumacher, A., Faust, C. & Magnuson, T. Positional cloning of a global regulator of anterior–posterior patterning in mice. Nature 383, 250–253 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Takihara, Y. et al. Targeted disruption of the mouse homologue of the Drosophila polyhomeotic gene leads to altered anteroposterior patterning and neural crest defects. Development 124, 3673–3682 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Negre, N. et al. Chromosomal distribution of PcG proteins during Drosophila development. PLoS Biol. 4, e170 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Tolhuis, B. et al. Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nature Genet. 38, 694–699 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Hombria, J. C. & Lovegrove, B. Beyond homeosis — HOX function in morphogenesis and organogenesis. Differentiation 71, 461–476 (2003).

    Article  PubMed  Google Scholar 

  64. Burch, J. B. Regulation of GATA gene expression during vertebrate development. Semin. Cell Dev. Biol. 16, 71–81 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Schepers, G. E., Teasdale, R. D. & Koopman, P. Twenty pairs of Sox: extent, homology, and nomenclature of the mouse and human Sox transcription factor gene families. Dev. Cell 3, 167–170 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Showell, C., Binder, O. & Conlon, F. L. T-box genes in early embryogenesis. Dev. Dyn. 229, 201–218 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Loebel, D. A., Watson, C. M., De Young, R. A. & Tam, P. P. Lineage choice and differentiation in mouse embryos and embryonic stem cells. Dev. Biol. 264, 1–14 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Bierie, B. & Moses, H. L. TGF-β and cancer. Cytokine Growth Factor Rev. 17, 29–40 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005). First comprehensive description of the core transcriptional network regulated by the pluripotency factors OCT4, SOX2 and Nanog in human ES cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chambers, I. et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643–655 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Mitsui, K. et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631–642 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Caretti, G., Di Padova, M., Micales, B., Lyons, G. E. & Sartorelli, V. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 18, 2627–2638 (2004). This study shows that EZH2 inhibits muscle cell differentiation in a histone methyltransferase-dependent manner by repressing muscle-specific genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen, X., Hiller, M., Sancak, Y. & Fuller, M. T. Tissue-specific TAFs counteract Polycomb to turn on terminal differentiation. Science 310, 869–872 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Klose, R. J. et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442, 312–316 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Voncken, J. W. et al. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status. J. Cell Sci. 112, 4627–4639 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Hernandez-Munoz, I. et al. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc. Natl Acad. Sci. USA 102, 7635–7640 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gunster, M. J. et al. Identification and characterization of interactions between the vertebrate Polycomb-group protein BMI1 and human homologs of polyhomeotic. Mol. Cell. Biol. 17, 2326–2335 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kagey, M. H., Melhuish, T. A. & Wotton, D. The Polycomb protein Pc2 is a SUMO E3. Cell 113, 127–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Collins, C. A. et al. Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 122, 289–301 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Kim, C. F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Montarras, D. et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309, 2064–2067 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Iwama, A. et al. Enhanced self-renewal of hematopoietic stem cells mediated by the Polycomb gene product Bmi-1. Immunity 21, 843–851 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003). An elegant study demonstrating that BMI1 is required for the proliferation of leukaemic stem cells.

    Article  CAS  PubMed  Google Scholar 

  91. Leung, C. et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428, 337–341 (2004). The authors show that BMI1 is essential for SHH-induced proliferation of cerebellar precursor cells and is implicated in medullablastoma pathogenesis.

    Article  CAS  PubMed  Google Scholar 

  92. Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Chagraoui, J. et al. E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells. Genes Dev. 20, 2110–2120 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kamminga, L. M. et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107, 2170–2179 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee, N., Maurange, C., Ringrose, L. & Paro, R. Suppression of Polycomb group proteins by JNK signalling induces transdetermination in Drosophila imaginal discs. Nature 438, 234–237 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Liu, S. et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66, 6063–6071 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hemmati, H. D. et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl Acad. Sci. USA 100, 15178–15183 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Singh, S. K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003).

    CAS  PubMed  Google Scholar 

  101. Pasca di Magliano, M. & Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nature Rev. Cancer 3, 903–911 (2003).

    Article  Google Scholar 

  102. Ferres-Marco, D. et al. Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430–436 (2006). A genetic screen identifying two epigenetic repressors as collaborators of Notch-induced tumour development.

    Article  CAS  PubMed  Google Scholar 

  103. Bruggeman, S. W. & van Lohuizen, M. Controlling stem cell proliferation: CKIs at work. Cell Cycle 5, 1281–1285 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Glinsky, G. V., Berezovska, O. & Glinskii, A. B. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J. Clin. Invest. 115, 1503–21 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    Article  CAS  Google Scholar 

  106. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Turner, B. M. Cellular memory and the histone code. Cell 111, 285–291 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Kanno, M., Hasegawa, M., Ishida, A., Isono, K. & Taniguchi, M. mel-18, a Polycomb group-related mammalian gene, encodes a transcriptional negative regulator with tumor suppressive activity. EMBO J. 14, 5672–5678 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dejardin, J. et al. Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1. Nature 434, 533–538 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Klymenko, T. & Muller, J. The histone methyltransferases Trithorax and Ash1 prevent transcriptional silencing by Polycomb group proteins. EMBO Rep. 5, 373–377 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Raman, J. D. et al. Increased expression of the Polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin. Cancer Res. 11, 8570–8576 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Arisan, S. et al. Increased expression of EZH2, a Polycomb group protein, in bladder carcinoma. Urol. Int. 75, 252–257 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Weikert, S. et al. Expression levels of the EZH2 Polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int. J. Mol. Med. 16, 349–353 (2005).

    CAS  PubMed  Google Scholar 

  115. Bachmann, I. M. et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol. 24, 268–273 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Raaphorst, F. M. et al. Poorly differentiated breast carcinoma is associated with increased expression of the human Polycomb group EZH2 gene. Neoplasia 5, 481–488 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Collett, K. et al. Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin. Cancer Res. 12, 1168–1174 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Mimori, K. et al. Clinical significance of enhancer of zeste homolog 2 expression in colorectal cancer cases. Eur. J. Surg. Oncol. 31, 376–380 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Sudo, T. et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br. J. Cancer 92, 1754–1758 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sawa, M. et al. BMI-1 is highly expressed in M0-subtype acute myeloid leukemia. Int. J. Hematol. 82, 42–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Bea, S. et al. BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res. 61, 2409–2412 (2001).

    CAS  PubMed  Google Scholar 

  122. Nowak, K. et al. BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas. Nucleic Acids Res. 34, 1745–1754 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Vonlanthen, S. et al. The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A–ARF locus expression. Br. J. Cancer 84, 1372–1376 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wang, S., Robertson, G. P. & Zhu, J. A novel human homologue of Drosophila Polycomblike gene is up-regulated in multiple cancers. Gene 343, 69–78 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Tokimasa, S. et al. Lack of the Polycomb-group gene rae28 causes maturation arrest at the early B-cell developmental stage. Exp. Hematol. 29, 93–103 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. Gilbert, S. F. in Developmental Biology 6th edn (Sinauer Associates, Sunderland, 2000).

    Google Scholar 

  127. Moazed, D. & O'Farrell, P. H. Maintenance of the engrailed expression pattern by Polycomb group genes in Drosophila. Development, 116, 805–810 (1992).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank members of the laboratory for critical review of the manuscript and for helpful discussions. We apologize to colleagues whose original work could not be cited owing to space constraints. This work was supported by a grant from the Ministerie van Onderwijs, Cultuur, Wetenschap (OCW) Besluit subsidies investeringen in den kennisinfrastructuur (BISK).

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Glossary

Chromatin fibre

The chromatin fibre consists of a highly dynamic array of nucleosomes, the basic repeating unit of chromatin. Each nucleosome is composed of 200 base pairs of DNA wrapped around an octamer of histone proteins; individual nucleosomes are connected by linker DNA.

Hox genes

A family of homeodomain-containing transcription factors that are conserved across all animals with bilateral symmetry; they are expressed in sequence along the anterior–posterior axis and are involved in conferring axial identity.

Chromodomain

A highly conserved sequence motif originally identified in the Drosophila melanogaster proteins Polycomb (PC) and Heterochromatin protein 1 (HP1). Chromodomain proteins are often components of large macromolecular complexes involved in regulating chromatin structure.

SWI/SNF complex

A chromatin-remodelling complex that was identified genetically in yeast as a group of genes required for mating type switching and growth on alternative sugar sources (sucrose non-fermenting mutants).

Axial patterning

The establishment of regional identities of cells and tissues along the developing anterior–posterior body axis.

Zygotic transcription factors

Transcriptional regulators that are expressed in the fertilized egg.

SUMO

Small ubiquitin-related modifier (SUMO) polypeptides are used to post-translationally modify cellular proteins in order to regulate their function and stability.

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Sparmann, A., van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6, 846–856 (2006). https://doi.org/10.1038/nrc1991

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