Review Article | Published:

SWI/SNF nucleosome remodellers and cancer

Nature Reviews Cancer volume 11, pages 481492 (2011) | Download Citation

Abstract

SWI/SNF chromatin remodelling complexes use the energy of ATP hydrolysis to remodel nucleosomes and to modulate transcription. Growing evidence indicates that these complexes have a widespread role in tumour suppression, as inactivating mutations in several SWI/SNF subunits have recently been identified at a high frequency in a variety of cancers. However, the mechanisms by which mutations in these complexes drive tumorigenesis are unclear. In this Review we discuss the contributions of SWI/SNF mutations to cancer formation, examine their normal functions and discuss opportunities for novel therapeutic interventions for SWI/SNF-mutant cancers.

Key points

  • Specific inactivating mutations in subunits of SWI/SNF chromatin remodelling complexes, including the SNF5 (also known as SMARCB1, INI1 and BAF47), ARID1A (also known as BAF250A and SMARCF1), BAF180 (also known as PBRM1) and BRM/SWI2-related gene 1 (BRG1; also known as SMARCA4) subunits, occur at a high frequency in several types of cancer.

  • Genetically engineered mice carrying mutations in Snf5 and Brg1 have established that at least some SWI/SNF subunits have bona fide tumour suppressor activity.

  • SWI/SNF complexes regulate gene expression by using the energy of ATP to remodel chromatin.

  • A central function of SWI/SNF complexes is the coordinated regulation of gene expression programmes. These complexes have essential roles during lineage specification and in the maintenance of stem cell pluripotency.

  • Emerging evidence has identified key pathways that contribute to tumorigenesis following perturbation of SWI/SNF complexes.

  • Collectively, enzymes that modify chromatin structure are emerging as key regulators of tumorigenesis. As epigenetic alterations are potentially reversible, unlike DNA mutations, the targeted inhibition of chromatin-modifying enzymes may have important therapeutic implications for cancer.

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References

  1. 1.

    Oncogenic role of “master” transcription factors in human leukemias and sarcomas: a developmental model. Adv. Cancer Res. 67, 25–57 (1995).

  2. 2.

    & Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae. Genetics 108, 845–858 (1984).

  3. 3.

    , & Five SWI genes are required for expression of the HO gene in yeast. J. Mol. Biol. 178, 853–868 (1984).

  4. 4.

    & Cell cycle control of the yeast HO gene: cis- and trans-acting regulators. Cell 48, 389–397 (1987).

  5. 5.

    , , , & Structural analysis of the yeast SWI/SNF chromatin remodeling complex. Nature Struct. Biol. 10, 141–145 (2003).

  6. 6.

    , , , & A multisubunit complex containing the SWI1/ADR6, SWI2/SNF2, SWI3, SNF5, and SNF6 gene products isolated from yeast. Proc. Natl Acad. Sci. USA 91, 1950–1954 (1994).

  7. 7.

    , , & Stimulation of GAL4 derivative binding to nucleosomal DNA by the yeast SWI/SNF complex. Science 265, 53–60 (1994).

  8. 8.

    et al. Differential targeting of two distinct SWI/SNF-related Drosophila chromatin-remodeling complexes. Mol. Cell Biol. 24, 3077–3088 (2004).

  9. 9.

    et al. The Drosophila trithorax group proteins, BRM, ASH1 and ASH2 are subunits of distinct protein complexes. Development 125, 3955–3966 (1998).

  10. 10.

    , , & Facilitated binding of TATA-binding protein to nucleosomal DNA. Nature 370, 481–485 (1994).

  11. 11.

    , , , & Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 370, 477–481 (1994). Along with reference 10, this paper describes the purification and characterization of nucleosome remodelling activity by mammalian SWI/SNF complexes.

  12. 12.

    & Composition and functional specificity of SWI2/SNF2 class chromatin remodeling complexes. Biochim. Biophys. Acta 1681, 59–73 (2005).

  13. 13.

    et al. RSC, an essential, abundant chromatin-remodeling complex. Cell 87, 1249–1260 (1996).

  14. 14.

    et al. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 15, 5370–5382 (1996).

  15. 15.

    , , & Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol. Cell 3, 247–253 (1999).

  16. 16.

    , , , , 3rd & BRD7, a novel PBAF-specific SWI/SNF subunit, is required for target gene activation and repression in embryonic stem cells. J. Biol. Chem. 283, 32254–32263 (2008).

  17. 17.

    et al. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem. J. 383, 319–325 (2004).

  18. 18.

    et al. The human SWI/SNF-B chromatin-remodeling complex is related to yeast rsc and localizes at kinetochores of mitotic chromosomes. Proc. Natl Acad. Sci. USA 97, 13015–13020 (2000).

  19. 19.

    et al. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development. Nature 432, 107–112 (2004).

  20. 20.

    , & Understanding the words of chromatin regulation. Cell 136, 200–206 (2009).

  21. 21.

    et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201–215 (2007). Demonstrates cell type-specific functions in vivo for variant subunits of the SWI/SNF complexes thus providing insight into the mechanism by which SWI/SNF complexes control lineage-specific development.

  22. 22.

    et al. BAF250B-associated SWI/SNF chromatin-remodeling complex is required to maintain undifferentiated mouse embryonic stem cells. Stem Cells 26, 1155–1165 (2008).

  23. 23.

    , & Chromatin remodelling: the industrial revolution of DNA around histones. Nature Rev. Mol. Cell Biol. 7, 437–447 (2006).

  24. 24.

    , & Mechanism of chromatin remodeling. Proc. Natl Acad. Sci. USA 107, 3458–3462 (2010).

  25. 25.

    et al. SWI/SNF has intrinsic nucleosome disassembly activity that is dependent on adjacent nucleosomes. Mol. Cell 38, 590–602 (2010).

  26. 26.

    et al. Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes. Nature 418, 195–199 (2002).

  27. 27.

    et al. An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network. Proc. Natl Acad. Sci. USA 106, 5187–5191 (2009).

  28. 28.

    et al. Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation. Proc. Natl Acad. Sci. USA 102, 17745–17750 (2005).

  29. 29.

    et al. Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5. Mol. Cell Biol. 22, 5975–5988 (2002).

  30. 30.

    et al. Genomic analysis using high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin. Cancer Res. 15, 1923–1930 (2009).

  31. 31.

    et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

  32. 32.

    et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74–79 (1999).

  33. 33.

    et al. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am. J. Hum. Genet. 65, 1342–1348 (1999).

  34. 34.

    et al. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am. J. Hum. Genet. 80, 805–810 (2007).

  35. 35.

    , , , & Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr. Blood Cancer 52, 328–334 (2009).

  36. 36.

    et al. SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma. Am. J. Surg. Pathol. 32, 1168–1174 (2008).

  37. 37.

    et al. Loss of INI1 expression defines a unique subset of pediatric undifferentiated soft tissue sarcomas. Mod. Pathol. 22, 142–150 (2009).

  38. 38.

    et al. SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res. 65, 4012–4019 (2005).

  39. 39.

    et al. Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. J. Med. Genet. 48, 93–97 (2011).

  40. 40.

    et al. Loss of SMARCB1/INI1 expression in poorly differentiated chordomas. Acta Neuropathol. 120, 745–753 (2010).

  41. 41.

    , , , & Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proc. Natl Acad. Sci. USA 97, 13796–13800 (2000).

  42. 42.

    et al. The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep. 1, 500–506 (2000).

  43. 43.

    et al. Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice. Mol. Cell Biol. 21, 3598–3603 (2001).

  44. 44.

    , , & Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell 2, 415–425 (2002).

  45. 45.

    et al. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nature Genet. 7, 480–484 (1994).

  46. 46.

    , , , & A human protein with homology to Saccharomyces cerevisiae SNF5 interacts with the potential helicase hbrm. Nucleic Acids Res. 23, 1127–1132 (1995).

  47. 47.

    , & Structure-function analysis of integrase interactor 1/hSNF5L1 reveals differential properties of two repeat motifs present in the highly conserved region. Proc. Natl Acad. Sci. USA 95, 1120–1125 (1998).

  48. 48.

    et al. P16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells. J. Biol. Chem. 279, 3807–3816 (2004).

  49. 49.

    et al. Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. Cancer Res. 69, 8094–8101 (2009).

  50. 50.

    et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

  51. 51.

    et al. BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer. Cancer Res. 68, 1667–1674 (2008).

  52. 52.

    et al. Polybromo protein BAF180 functions in mammalian cardiac chamber maturation. Genes Dev. 18, 3106–3116 (2004).

  53. 53.

    et al. A specificity and targeting subunit of a human SWI/SNF family-related chromatin-remodeling complex. Mol. Cell Biol. 20, 8879–8888 (2000).

  54. 54.

    , , & Selectivity of chromatin-remodelling cofactors for ligand-activated transcription. Nature 414, 924–928 (2001).

  55. 55.

    Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91, 309–319 (2009).

  56. 56.

    , , & Functional differentiation of SWI/SNF remodelers in transcription and cell cycle control. Mol. Cell Biol. 27, 651–661 (2007).

  57. 57.

    et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).

  58. 58.

    et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).

  59. 59.

    et al. The Genetic Landscape of the Childhood Cancer Medulloblastoma. Science 331, 435–439 (2011).

  60. 60.

    , , , & Genomic and functional evidence for an ARID1A tumor suppressor role. Genes Chromosom. Cancer 46, 745–750 (2007).

  61. 61.

    et al. The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia. J. Natl Cancer Inst. 100, 1792–1803 (2008).

  62. 62.

    et al. Expression of SMARCB1 modulates steroid sensitivity in human lymphoblastoid cells: identification of a promoter SNP that alters PARP1 binding and SMARCB1 expression. Hum. Mol. Genet. 16, 2261–2271 (2007).

  63. 63.

    et al. The DNA-binding properties of the ARID-containing subunits of yeast and mammalian SWI/SNF complexes. Nucleic Acids Res. 32, 1345–1353 (2004).

  64. 64.

    et al. The p270 (ARID1A/SMARCF1) subunit of mammalian SWI/SNF-related complexes is essential for normal cell cycle arrest. Cancer Res. 65, 9236–9244 (2005).

  65. 65.

    , , , & Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res. 63, 560–566 (2003).

  66. 66.

    et al. Chromatin remodeling factors and BRM/BRG1 expression as prognostic indicators in non-small cell lung cancer. Clin. Cancer Res. 10, 4314–4324 (2004).

  67. 67.

    et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum. Mutat. 29, 617–622 (2008).

  68. 68.

    et al. Mutation analysis of the BRG1 gene in prostate cancer clinical samples. Int. J. Oncol. 22, 1003–1007 (2003).

  69. 69.

    et al. Genetic and epigenetic alterations of BRG1 promote oral cancer development. Int. J. Oncol. 26, 201–210 (2005).

  70. 70.

    et al. Genetic and epigenetic screening for gene alterations of the chromatin-remodeling factor, SMARCA4/BRG1, in lung tumors. Genes Chromosom. Cancer 41, 170–177 (2004).

  71. 71.

    et al. BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Res. 60, 6171–6177 (2000).

  72. 72.

    et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum. Mutat. 32, E1999–E2017 (2011).

  73. 73.

    et al. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am. J. Hum. Genet. 86, 279–284 (2010).

  74. 74.

    et al. Characterization of mammary tumors from Brg1 heterozygous mice. Oncogene 27, 460–468 (2008).

  75. 75.

    et al. A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol. Cell 6, 1287–1295 (2000).

  76. 76.

    , , , & Targeted knockout of BRG1 potentiates lung cancer development. Cancer Res. 68, 3689–3696 (2008).

  77. 77.

    et al. Altered control of cellular proliferation in the absence of mammalian brahma (SNF2α). EMBO J. 17, 6979–6991 (1998).

  78. 78.

    , , & Antagonistic roles for BRM and BRG1 SWI/SNF complexes in differentiation. J. Biol. Chem. 284, 10067–10075 (2009).

  79. 79.

    & Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes. Mol. Cell 11, 377–389 (2003). Along with reference 78 this paper shows that BRG1 and BRM, the catalytic ATPase subunits of SWI/SNF complexes, can have distinct roles in regulating transcription.

  80. 80.

    et al. The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer. Cancer Res. 68, 10154–10162 (2008).

  81. 81.

    et al. The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene 26, 7058–7066 (2007). Along with references 77 and 80 this paper supports epigenetic silencing of BRM as driver of cancer formation.

  82. 82.

    et al. BRD7 is a candidate tumour suppressor gene required for p53 function. Nature Cell Biol. 12, 380–389 (2010).

  83. 83.

    , & Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence. Proc. Natl Acad. Sci. USA 107, 14280–14285 (2010).

  84. 84.

    et al. SWI/SNF chromatin remodeling complex is obligatory for BMP2-induced, Runx2-dependent skeletal gene expression that controls osteoblast differentiation. J. Cell Biochem. 94, 720–730 (2005).

  85. 85.

    , & Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers. Nature Rev. Genet. 7, 461–473 (2006).

  86. 86.

    et al. Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56, 94–108 (2007).

  87. 87.

    et al. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc. Natl Acad. Sci. USA 106, 5181–5186 (2009).

  88. 88.

    , & SWI/SNF-Brg1 regulates self-renewal and occupies core pluripotency-related genes in embryonic stem cells. Stem Cells 27, 317–328 (2009).

  89. 89.

    et al. ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a. Proc. Natl Acad. Sci. USA 105, 6656–6661 (2008).

  90. 90.

    et al. Chromatin-remodeling components of the BAF complex facilitate reprogramming. Cell 141, 943–955 (2010).

  91. 91.

    et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316–328 (2010).

  92. 92.

    & Yeast SNF/SWI transcriptional activators and the SPT/SIN chromatin connection. Trends Genet. 8, 387–391 (1992).

  93. 93.

    , & Hormone-response genes are direct in vivo regulatory targets of Brahma (SWI/SNF) complex function. J. Biol. Chem. 281, 35305–35315 (2006).

  94. 94.

    et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol. Cell 29, 611–624 (2008).

  95. 95.

    et al. INI1 induces interferon signaling and spindle checkpoint in rhabdoid tumors. Clin. Cancer Res. 13, 4721–4730 (2007).

  96. 96.

    et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009). This paper elucidates roles for SWI/SNF complexes in regulating inducible transcription and finds differential roles at CpG versus non-CpG island genes.

  97. 97.

    & Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila. Proc. Natl Acad. Sci. USA 85, 8136–8140 (1988).

  98. 98.

    et al. brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68, 561–572 (1992).

  99. 99.

    & The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev. 14, 155–164 (2004).

  100. 100.

    The Polycomb and trithorax group proteins of Drosophila: trans-regulators of homeotic gene function. Annu. Rev. Genet. 29, 289–303 (1995).

  101. 101.

    et al. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 98, 37–46 (1999).

  102. 102.

    & Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647, 21–29 (2008).

  103. 103.

    , , & SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus. Mol. Cell Biol. 28, 3457–3464 (2008). Along with reference 91, this paper establishes an epigenetic antagonistic relationship between Polycomb and SWI/SNF complexes, which is essential for oncogenic transformation driven by SNF5 loss.

  104. 104.

    et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell 18, 185–197 (2010).

  105. 105.

    et al. The enhancer of zeste homolog 2 gene contributes to cell proliferation and apoptosis resistance in renal cell carcinoma cells. Int. J. Cancer 123, 1545–1550 (2008).

  106. 106.

    , , , & RB and hbrm cooperate to repress the activation functions of E2F1. Proc. Natl Acad. Sci. USA 94, 11268–11273 (1997).

  107. 107.

    , , & E2F target genes: unraveling the biology. Trends Biochem. Sci. 29, 409–417 (2004).

  108. 108.

    , , & A key role of the hSNF5/INI1 tumour suppressor in the control of the G1-S transition of the cell cycle. Oncogene 21, 6403–6412 (2002).

  109. 109.

    et al. Functional interaction of the retinoblastoma and Ini1/Snf5 tumor suppressors in cell growth and pituitary tumorigenesis. Cancer Res. 66, 8076–8082 (2006).

  110. 110.

    et al. Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instability. Mol. Cell Biol. 28, 6223–6233 (2008).

  111. 111.

    , , , & Genetic ablation of Cyclin D1 abrogates genesis of rhabdoid tumors resulting from Ini1 loss. Proc. Natl Acad. Sci. USA 102, 12129–12134 (2005). This paper identifies cyclin D1 downregulation as a mechanism driving SNF5-deficient cancers.

  112. 112.

    , , & Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. Lab. Invest. 90, 724–738 (2010).

  113. 113.

    , , & Systematic analysis of the antiproliferative effects of novel and standard anticancer agents in rhabdoid tumor cell lines. Anticancer Drugs 21, 514–522 (2010).

  114. 114.

    et al. Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors. Oncogene 25, 722–734 (2006).

  115. 115.

    et al. Therapeutically targeting cyclin D1 in primary tumors arising from loss of Ini1. Proc. Natl Acad. Sci. USA 108, 319–324 (2011).

  116. 116.

    et al. c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function. Nature Genet. 22, 102–105 (1999).

  117. 117.

    , , , & The c-myc gene is a direct target of mammalian SWI/SNF-related complexes during differentiation-associated cell cycle arrest. Cancer Res. 66, 1289–1293 (2006).

  118. 118.

    , , , & Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle control. EMBO J. 26, 752–763 (2007).

  119. 119.

    & The BRG1 transcriptional coregulator. Nucl. Recept Signal 6, e004 (2008).

  120. 120.

    & Regulating SWI/SNF subunit levels via protein-protein interactions and proteasomal degradation: BAF155 and BAF170 limit expression of BAF57. Mol. Cell Biol. 25, 9016–9027 (2005).

  121. 121.

    & Reconstitution of glucocorticoid receptor-dependent transcription in vivo. Mol. Cell Biol. 24, 3347–3358 (2004).

  122. 122.

    et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nature Med. 16, 1429–1433 (2010). This paper identifies aberrant activation of the HH–Gli pathway as a driving mechanism in SNF5-deficient cancers.

  123. 123.

    , & RhoA-dependent regulation of cell migration by the tumor suppressor hSNF5/INI1. Cancer Res. 68, 6154–6161 (2008).

  124. 124.

    , , & Rho GTPase function in tumorigenesis. Biochim. Biophys. Acta 1796, 91–98 (2009).

  125. 125.

    , , & BRG1 loss in MiaPaCa2 cells induces an altered cellular morphology and disruption in the organization of the actin cytoskeleton. J. Cell Physiol. 205, 286–294 (2005).

  126. 126.

    , , & Expression of BRG1, a human SWI/SNF component, affects the organisation of actin filaments through the RhoA signalling pathway. J. Cell Sci. 115, 2735–2746 (2002).

  127. 127.

    et al. The BRG-1 subunit of the SWI/SNF complex regulates CD44 expression. J. Bio. Chem. 276, 9273–9278 (2001).

  128. 128.

    et al. Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression. Oncogene 21, 1196–1207 (2002). Along with references 31, 50, 57 and 58 this paper demonstrates that subunits of SWI/SNF complexes are specifically mutated and inactivated in a variety of human cancers.

  129. 129.

    Chromatin remodelling and actin organisation. FEBS Lett. 582, 2041–2050 (2008).

  130. 130.

    & The fundamental role of epigenetic events in cancer. Nature Rev. Genet. 3, 415–428 (2002).

  131. 131.

    , & Increased DNA damage sensitivity and apoptosis in cells lacking the Snf5/Ini1 subunit of the SWI/SNF chromatin remodeling complex. Mol. Cell Biol. 26, 2661–2674 (2006).

  132. 132.

    et al. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction. EMBO J. 25, 3986–3997 (2006).

  133. 133.

    , & Chromatin remodeling and cancer, Part I: Covalent histone modifications. Trends Mol. Med. 13, 363–372 (2007).

  134. 134.

    et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nature Genet. 41, 465–472 (2009).

  135. 135.

    , & Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling. Trends Mol. Med. 13, 373–380 (2007).

  136. 136.

    & ATP-dependent chromatin remodeling in neural development. Curr. Opin. Neurobiol. 19, 120–126 (2009).

  137. 137.

    et al. Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis. Clin. Genet. 74, 358–366 (2008).

  138. 138.

    et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J. Med. Genet. 45, 332–339 (2008).

  139. 139.

    , , , & Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Hum. Mutat. 29, 227–231 (2008).

  140. 140.

    et al. INI1 mutations in meningiomas at a potential hotspot in exon 9. Br. J. Cancer 84, 199–201 (2001).

  141. 141.

    et al. Molecular heterogeneity of meningioma with INI1 mutation. Mol. Pathol. 56, 299–301 (2003).

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Acknowledgements

The authors especially thank E. McKenna, L. Mora-Blanco and S. Jhaveri-Schneider for critical reading of the manuscript and for helpful discussions.

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  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Children's Hospital Boston, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.

    • Boris G. Wilson
    •  & Charles W. M. Roberts

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Competing interests

C.W.M.R. is a recipient of a Dana-Farber Cancer Institute/Novartis Drug Discovery Grant and receives consulting fees from the Novartis Institute of Biomedical Research. B.G.W. declares no competing financial interests.

Corresponding author

Correspondence to Charles W. M. Roberts.

Glossary

Polycomb group (PcG) proteins

These proteins covalently modify histones and have roles in regulating gene expression during essential cell fate decisions. They have been divided into families based on biochemical purifications into two distinct complexes: polycomb repressive complex 1 (PRC1) and PRC2. The catalytic subunit of the PRC2 complexes EZH2 mediates trimethylation of histone H3 at lysine 27, which in turn is a histone binding site for PRC1 complexes, cooperatively leading to the formation of a repressive chromatin environment.

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