Polycomb silencers control cell fate, development and cancer

Nature Reviews Cancer

Volumn 6, Issue 11, 2006, Pages 846-856

  Sparmann, Anke ^a   Van Lohuizen, Maarten ^a  

^a NETHERLANDS CANCER INSTITUTE   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

EMBRYONIC ECTODERM DEVELOPMENT PROTEIN;

CANCER STEM CELL; CARCINOGENESIS; CARCINOGENICITY; CELL DIFFERENTIATION; CELL FATE; CELL FUNCTION; CELL MATURATION; EPIGENETICS; GENE SILENCING; HUMAN; HUMAN CELL; PRIORITY JOURNAL; REVIEW;

ANIMALS; APOPTOSIS; GENE SILENCING; HUMANS; NEOPLASMS; REPRESSOR PROTEINS;

EID: 33750379420     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1991     Document Type: Review

References (127)

1. Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nature Rev. Genet. 3, 415-428 (2002).
2. Martinez, A. M. & Cavalli, G. The role of Polycomb group proteins in cell cycle regulation during development. Cell Cycle 5, 1189-1197 (2006).
3. Valk-Lingbeek, M. E., Bruggeman, S. W. & van Lohuizen, M. Stem cells and cancer; the Polycomb connection. Cell 118, 409-418 (2004).
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).
5. Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and trithorax group proteins. Annu. Rev. Genet. 38, 413-443 (2004).
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).
7. Core, N. et al. Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development 124, 721-729 (1997).
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).
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).
10. Levine, S. S., King, I. F. & Kingston, R. E. Division of labor in Polycomb group repression. Trends Biochem. Sci. 29, 478-485 (2004).
11. Lund, A. H. & van Lohuizen, M. Polycomb complexes and silencing mechanisms. Curr. Opin. Cell Biol. 16, 239-246 (2004).
12. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039-1043 (2002).
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).
14. Muller, J. et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197-208 (2002).
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).
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).
17. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873-878 (2004).
18. Francis, N. J., Kingston, R. E. & Woodcock, C. L. Chromatin compaction by a Polycomb group protein complex. Science 306, 1574-1577 (2004).
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).
20. Schwartz, Y. B. et al. Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nature Genet. 38, 700-705 (2006).
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).
22. Grimaud, C. et al. RNAi components are required for nuclear clustering of Polycomb group response elements. Cell 124, 957-971 (2006).
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).
24. Dellino, G. I. et al. Polycomb silencing blocks transcription initiation. Mol. Cell 13, 887-893 (2004).
25. Francis, N. J. & Kingston, R. E. Mechanisms of transcriptional memory. Nature Rev. Mol. Cell Biol. 2, 409-421 (2001).
26. Wang, L. et al. Hierarchical recruitment of Polycomb group silencing complexes. Mol. Cell 14, 637-646 (2004).
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).
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.
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).
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.
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).
32. van Lohuizen, M. et al. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 65, 737-752 (1991).
33. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycombgroup gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164-168 (1999).
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.
35. Sherr, C. J. The INK4a/ARF network in tumour suppression. Nature Rev. Mol. Cell Biol. 2, 731-737 (2001).
36. Lowe, S. W. & Sherr, C. J. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr. Opin. Genet. Dev. 13, 77-83 (2003).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
47. Varambally, S. et al. The Polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624-629 (2002).
48. Su, I. H. et al. Polycomb group protein EZH2 controls actin polymerization and cell signaling. Cell 121, 425-436 (2005).
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).
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).
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.
52. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349-353 (2006).
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.
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).
55. Meshorer, E. & Misteli, T. Chromatin in pluripotent embryonic stem cells and differentiation. Nature Rev. Mol. Cell Biol. 7, 540-546 (2006).
56. Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nature Cell Biol. 8, 532-538 (2006).
57. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315-326 (2006).
58. O'Carroll, D. et al. The Polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330-4336 (2001).
59. Shumacher, A., Faust, C. & Magnuson, T. Positional cloning of a global regulator of anterior-posterior patterning in mice. Nature 383, 250-253 (1996).
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).
61. Negre, N. et al. Chromosomal distribution of PcG proteins during Drosophila development. PLoS Biol. 4, e170 (2006).
62. Tolhuis, B. et al. Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nature Genet. 38, 694-699 (2006).
63. Hombria, J. C. & Lovegrove, B. Beyond homeosis - HOX function in morphogenesis and organogenesis. Differentiation 71, 461-476 (2003).
64. Burch, J. B. Regulation of GATA gene expression during vertebrate development. Semin. Cell Dev. Biol. 16, 71-81 (2005).
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).
66. Showell, C., Binder, O. & Conlon, F. L. T-box genes in early embryogenesis. Dev. Dyn. 229, 201-218 (2004).
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).
68. Bierie, B. & Moses, H. L. TGF-β and cancer. Cytokine Growth Factor Rev. 17, 29-40 (2006).
69. Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843-850 (2005).
70. Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126-140 (2003).
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.
72. Chambers, I. et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643-655 (2003).
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).
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).
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.
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).
77. Klose, R. J. et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442, 312-316 (2006).
78. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941-953 (2004).
79. Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811-816 (2006).
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).
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).
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).
83. Kagey, M. H., Melhuish, T. A. & Wotton, D. The Polycomb protein Pc2 is a SUMO E3. Cell 113, 127-137 (2003).
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).
85. Kim, C. F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823-835 (2005).
86. Montarras, D. et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309, 2064-2067 (2005).
87. Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84-88 (2006).
88. Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993-997 (2006).
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).
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.
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.
92. Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962-967 (2003).
93. Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302-305 (2003).
94. Chagraoui, J. et al. E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells. Genes Dev. 20, 2110-2120 (2006).
95. Kamminga, L. M. et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107, 2170-2179 (2006).
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).
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).
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).
99. Hemmati, H. D. et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl Acad. Sci. USA 100, 15178-15183 (2003).
100. Singh, S. K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821-5828 (2003).
101. Pasca di Magliano, M. & Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nature Rev. Cancer 3, 903-911 (2003).
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.
103. Bruggeman, S. W. & van Lohuizen, M. Controlling stem cell proliferation: CKIs at work. Cell Cycle 5, 1281-1285 (2006).
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).
105. van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530-536 (2002).
106. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41-45 (2000).
107. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074-1080 (2001).
108. Turner, B. M. Cellular memory and the histone code. Cell 111, 285-291 (2002).
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).
110. Dejardin, J. et al. Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1. Nature 434, 533-538 (2005).
111. Klymenko, T. & Muller, J. The histone methyltransferases Trithorax and Ash1 prevent transcriptional silencing by Polycomb group proteins. EMBO Rep. 5, 373-377 (2004).
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).
113. Arisan, S. et al. Increased expression of EZH2, a Polycomb group protein, in bladder carcinoma. Urol. Int. 75, 252-257 (2005).
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).
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).
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).
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).
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).
119. Sudo, T. et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br. J. Cancer 92, 1754-1758 (2005).
120. Sawa, M. et al. BMI-1 is highly expressed in M0-subtype acute myeloid leukemia. Int. J. Hematol. 82, 42-47 (2005).
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).
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).
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).
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).
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).
126. Gilbert, S. F. in Developmental Biology 6th edn (Sinauer Associates, Sunderland, 2000).
127. Moazed, D. & O'Farrell, P. H. Maintenance of the engrailed expression pattern by Polycomb group genes in Drosophila. Development, 116, 805-810 (1992).