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Chromatin Biology and Cancer Linked Through Protein–Protein Interactions

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Systems Analysis of Chromatin-Related Protein Complexes in Cancer

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Abstract

Up-to-date human protein–protein interaction (PPI) networks for chromatin modification (CM) proteins are constructed and analyzed to explore the functional link between cancer and chromatin-modifying enzymes (CME), such as histone acetyltransferases (HAT), histone deacetylases (HDAC), histone methyltransferases (HMT), histone demethylases (HDM), and DNA-modifying enzymes (DME, including DNA methyltransferases and methylcytosine dioxygenases). In a high-confidence human CM network, extensive interactions (physical associations) are found among CMEs, indicating that CMEs regulate and cooperate with each other to produce complex epigenetic marks. Our results also show that neighbors (interaction partners) of CMEs are enriched not only with proteins involved in transcription (transcription factors and cofactors) but also with proteins coded by oncogenes, tumor suppressor genes, and cancer genes. It is highly likely that products of oncogenes and tumor suppressor genes control gene expression at least in part by regulating the activities of CMEs and that dys-regulation of CMEs plays an important role in tumorigenesis. In addition to drugs targeting CMEs and chromatin readers, drugs targeting process-specific regulators (activators, inhibitors, and recruiters) of CMEs may provide effective and selective alternatives for epigenetic cancer therapy. Identification and characterization of CME regulators should be a top priority in epigenetics and cancer research.

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References

  1. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128:635–8.

    Article  PubMed  CAS  Google Scholar 

  2. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705.

    Article  PubMed  CAS  Google Scholar 

  3. Elsasser SJ, Allis CD, Lewis PW. Cancer. New epigenetic drivers of cancers. Science. 2011;331:1145–6.

    Article  PubMed  CAS  Google Scholar 

  4. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2011;39:D945–50.

    Article  PubMed  CAS  Google Scholar 

  5. Chi P, Allis CD, Wang GG. Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer. 2010;10:457–69.

    Article  PubMed  CAS  Google Scholar 

  6. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31:27–36.

    Article  PubMed  CAS  Google Scholar 

  7. Cross NC. Histone modification defects in developmental disorders and cancer. Oncotarget. 2012;3:3–4.

    PubMed  Google Scholar 

  8. Hake SB, Xiao A, Allis CD. Linking the epigenetic ‘language’ of covalent histone modifications to cancer. Br J Cancer. 2007;96(Suppl):R31–9.

    PubMed  Google Scholar 

  9. Kouzarides T. Wellcome Trust Award Lecture. Chromatin-modifying enzymes in transcription and cancer. Biochem Soc Trans. 2003;31:741–3.

    Article  PubMed  CAS  Google Scholar 

  10. Wodak SJ, Pu S, Vlasblom J, Seraphin B. Challenges and rewards of interaction proteomics. Mol Cell Proteomics. 2009;8:3–18.

    Article  PubMed  CAS  Google Scholar 

  11. Babu M, Vlasblom J, Pu S, Guo X, Graham C, Bean BD, et al. Interaction landscape of membrane-protein complexes in Saccharomyces cerevisiae. Nature. 2012;489:585–9.

    Article  PubMed  CAS  Google Scholar 

  12. Collins SR, Kemmeren P, Zhao XC, Greenblatt JF, Spencer F, Holstege FC, et al. Toward a comprehensive atlas of the physical interactome of Saccharomyces cerevisiae. Mol Cell Proteomics. 2007;6:439–50.

    PubMed  CAS  Google Scholar 

  13. Gavin AC, Aloy P, Grandi P, Krause R, Boesche M, Marzioch M, et al. Proteome survey reveals modularity of the yeast cell machinery. Nature. 2006;440:631–6.

    Article  PubMed  CAS  Google Scholar 

  14. Krogan NJ, Cagney G, Yu H, Zhong G, Guo X, Ignatchenko A, et al. Global landscape of protein complexes in the yeast Saccharomyces cerevisiae. Nature. 2006;440:637–43.

    Article  PubMed  CAS  Google Scholar 

  15. Yu H, Braun P, Yildirim MA, Lemmens I, Venkatesan K, Sahalie J, et al. High-quality binary protein interaction map of the yeast interactome network. Science. 2008;322:104–10.

    Article  PubMed  CAS  Google Scholar 

  16. Li S, Armstrong CM, Bertin N, Ge H, Milstein S, Boxem M, et al. A map of the interactome network of the metazoan C. elegans. Science. 2004;303:540–3.

    Article  PubMed  CAS  Google Scholar 

  17. Guruharsha KG, Rual JF, Zhai B, Mintseris J, Vaidya P, Vaidya N, et al. A protein complex network of Drosophila melanogaster. Cell. 2011;147:690–703.

    Article  PubMed  CAS  Google Scholar 

  18. Havugimana PC, Hart GT, Nepusz T, Yang H, Turinsky AL, Li Z, et al. A census of human soluble protein complexes. Cell. 2012;150:1068–81.

    Article  PubMed  CAS  Google Scholar 

  19. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. Towards a proteome-scale map of the human protein-protein interaction network. Nature. 2005;437:1173–8.

    Article  PubMed  CAS  Google Scholar 

  20. Bader GD, Betel D, Hogue CW. BIND: the Biomolecular Interaction Network Database. Nucleic Acids Res. 2003;31:248–50.

    Article  PubMed  CAS  Google Scholar 

  21. Stark C, Breitkreutz BJ, Reguly T, Boucher L, Breitkreutz A, Tyers M. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 2006;34:D535–9.

    Article  PubMed  CAS  Google Scholar 

  22. Xenarios I, Salwinski L, Duan XJ, Higney P, Kim SM, Eisenberg D. DIP, the Database of Interacting Proteins: a research tool for studying cellular networks of protein interactions. Nucleic Acids Res. 2002;30:303–5.

    Article  PubMed  CAS  Google Scholar 

  23. Kerrien S, Alam-Faruque Y, Aranda B, Bancarz I, Bridge A, Derow C, et al. IntAct–open source resource for molecular interaction data. Nucleic Acids Res. 2007;35:D561–5.

    Article  PubMed  CAS  Google Scholar 

  24. Razick S, Magklaras G, Donaldson IM. iRefIndex: a consolidated protein interaction database with provenance. BMC Bioinformatics. 2008;9:405.

    Article  PubMed  Google Scholar 

  25. Turner B, Razick S, Turinsky AL, Vlasblom J, Crowdy EK, Cho E, et al. iRefWeb: interactive analysis of consolidated protein interaction data and their supporting evidence. Database (Oxford). 2010;2010:baq023.

    Article  Google Scholar 

  26. Chatr-aryamontri A, Ceol A, Palazzi LM, Nardelli G, Schneider MV, Castagnoli L, et al. MINT: the Molecular INTeraction database. Nucleic Acids Res. 2007;35:D572–4.

    Article  PubMed  CAS  Google Scholar 

  27. Guldener U, Munsterkotter M, Oesterheld M, Pagel P, Ruepp A, Mewes HW, et al. MPact: the MIPS protein interaction resource on yeast. Nucleic Acids Res. 2006;34:D436–41.

    Article  PubMed  Google Scholar 

  28. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.

    Article  PubMed  CAS  Google Scholar 

  29. Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, et al. New nomenclature for chromatin-modifying enzymes. Cell. 2007;131:633–6.

    Article  PubMed  CAS  Google Scholar 

  30. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12–27.

    Article  PubMed  CAS  Google Scholar 

  31. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95.

    Article  PubMed  CAS  Google Scholar 

  32. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–9.

    Article  PubMed  CAS  Google Scholar 

  33. Turinsky AL, Turner B, Borja RC, Gleeson JA, Heath M, Pu S, et al. DAnCER: disease-annotated chromatin epigenetics resource. Nucleic Acids Res. 2011;39:D889–94.

    Article  PubMed  CAS  Google Scholar 

  34. On T, Xiong X, Pu S, Turinsky A, Gong Y, Emili A, et al. The evolutionary landscape of the chromatin modification machinery reveals lineage specific gains, expansions, and losses. Proteins. 2010;78:2075–89.

    PubMed  CAS  Google Scholar 

  35. Pu S, Turinsky AL, Vlasblom J, On T, Xiong X, Emili A, et al. Expanding the landscape of chromatin modification (CM)-related functional domains and genes in human. PLoS One. 2010;5:e14122.

    Article  PubMed  CAS  Google Scholar 

  36. Kouzarides T. SnapShot: Histone-modifying enzymes. Cell. 2007;131:822.

    Article  PubMed  CAS  Google Scholar 

  37. Fields S, Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989;340:245–6.

    Article  PubMed  CAS  Google Scholar 

  38. Stagljar I, Korostensky C, Johnsson N, te Heesen S. A genetic system based on split-ubiquitin for the analysis of interactions between membrane proteins in vivo. Proc Natl Acad Sci USA. 1998;95:5187–92.

    Article  PubMed  CAS  Google Scholar 

  39. Puig O, Caspary F, Rigaut G, Rutz B, Bouveret E, Bragado-Nilsson E, et al. The tandem affinity purification (TAP) method: a general procedure of protein complex purification. Methods. 2001;24:218–29.

    Article  PubMed  CAS  Google Scholar 

  40. Malovannaya A, Lanz RB, Jung SY, Bulynko Y, Le NT, Chan DW, et al. Analysis of the human endogenous coregulator complexome. Cell. 2011;145:787–99.

    Article  PubMed  CAS  Google Scholar 

  41. Turinsky AL, Razick S, Turner B, Donaldson IM, Wodak SJ. Literature curation of protein interactions: measuring agreement across major public databases. Database (Oxford). 2010;2010:baq026.

    Article  Google Scholar 

  42. Turinsky AL, Razick S, Turner B, Donaldson IM, Wodak SJ. Interaction databases on the same page. Nat Biotechnol. 2011;29:391–3.

    Article  PubMed  CAS  Google Scholar 

  43. Ruepp A, Brauner B, Dunger-Kaltenbach I, Frishman G, Montrone C, Stransky M, et al. CORUM: the comprehensive resource of mammalian protein complexes. Nucleic Acids Res. 2008;36:D646–50.

    Article  PubMed  CAS  Google Scholar 

  44. Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13:484–92.

    Article  PubMed  CAS  Google Scholar 

  45. Qin W, Leonhardt H, Pichler G. Regulation of DNA methyltransferase 1 by interactions and modifications. Nucleus. 2011;2:392–402.

    Article  PubMed  Google Scholar 

  46. Clements EG, Mohammad HP, Leadem BR, Easwaran H, Cai Y, Van Neste L, et al. DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes. Nucleic Acids Res. 2012;40:4334–46.

    Article  PubMed  CAS  Google Scholar 

  47. Fuks F, Hurd PJ, Deplus R, Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003;31:2305–12.

    Article  PubMed  CAS  Google Scholar 

  48. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet. 2000;25:338–42.

    Article  PubMed  CAS  Google Scholar 

  49. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet. 2000;25:269–77.

    Article  PubMed  CAS  Google Scholar 

  50. Lee B, Muller MT. SUMOylation enhances DNA methyltransferase 1 activity. Biochem J. 2009;421:449–61.

    Article  PubMed  CAS  Google Scholar 

  51. Oh YM, Kwon YE, Kim JM, Bae SJ, Lee BK, Yoo SJ, et al. Chfr is linked to tumour metastasis through the downregulation of HDAC1. Nat Cell Biol. 2009;11:295–302.

    Article  PubMed  CAS  Google Scholar 

  52. Grimes JA, Nielsen SJ, Battaglioli E, Miska EA, Speh JC, Berry DL, et al. The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. J Biol Chem. 2000;275:9461–7.

    Article  PubMed  CAS  Google Scholar 

  53. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer. 2008;8:671–82.

    Article  PubMed  CAS  Google Scholar 

  54. Manning AL, Dyson NJ. pRB, a tumor suppressor with a stabilizing presence. Trends Cell Biol. 2011;21:433–41.

    Article  PubMed  CAS  Google Scholar 

  55. Maurer-Stroh S, Dickens NJ, Hughes-Davies L, Kouzarides T, Eisenhaber F, Ponting CP. The Tudor domain ‘Royal Family’: Tudor, plant Agenet, Chromo, PWWP and MBT domains. Trends Biochem Sci. 2003;28:69–74.

    Article  PubMed  CAS  Google Scholar 

  56. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol. 2007;14:1025–40.

    Article  PubMed  CAS  Google Scholar 

  57. Wang Y, Fischle W, Cheung W, Jacobs S, Khorasanizadeh S, Allis CD. Beyond the double helix: writing and reading the histone code. Novartis Found Symp. 2004;259:3–17. discussion 17–21, 163–169.

    Article  PubMed  CAS  Google Scholar 

  58. Maere S, Heymans K, Kuiper M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 2005;21:3448–9.

    Article  PubMed  CAS  Google Scholar 

  59. Higgins ME, Claremont M, Major JE, Sander C, Lash AE. CancerGenes: a gene selection resource for cancer genome projects. Nucleic Acids Res. 2007;35:D721–6.

    Article  PubMed  CAS  Google Scholar 

  60. Maglott D, Ostell J, Pruitt KD, Tatusova T. Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res. 2011;39:D52–7.

    Article  PubMed  CAS  Google Scholar 

  61. Becker KG, Barnes KC, Bright TJ, Wang SA. The genetic association database. Nat Genet. 2004;36:431–2.

    Article  PubMed  CAS  Google Scholar 

  62. Thorn CF, Klein TE, Altman RB. Pharmacogenomics and bioinformatics: PharmGKB. Pharmacogenomics. 2010;11:501–5.

    Article  PubMed  CAS  Google Scholar 

  63. Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell. 2010;19:698–711.

    Article  PubMed  CAS  Google Scholar 

  64. Seton-Rogers S. Lymphoma: Epigenetic therapy gains momentum. Nat Rev Cancer. 2012;12:798–9.

    Article  PubMed  CAS  Google Scholar 

  65. Rius M, Lyko F. Epigenetic cancer therapy: rationales, targets and drugs. Oncogene. 2012;31:4257–65.

    Article  PubMed  CAS  Google Scholar 

  66. Lustberg MB, Ramaswamy B. Epigenetic therapy in breast cancer. Curr Breast Cancer Rep. 2011;3:34–43.

    Article  PubMed  CAS  Google Scholar 

  67. Filosa A, Fabiani A. Epigenetic therapy in cancer: perspective and paradoxes. Anal Quant Cytol Histol. 2011;33:303–4.

    PubMed  Google Scholar 

  68. Amato RJ, Stephenson J, Hotte S, Nemunaitis J, Belanger K, Reid G, et al. MG98, a second-generation DNMT1 inhibitor, in the treatment of advanced renal cell carcinoma. Cancer Invest. 2012;30:415–21.

    Article  PubMed  CAS  Google Scholar 

  69. Dhawan D., Ramos-Vara JA., Hahn NM, Waddell J, Olbricht GR, Zheng R, Stewart JC, Knapp DW. DNMT1: An emerging target in the treatment of invasive urinary bladder cancer. Urol Oncol 2012.

    Google Scholar 

  70. Federico M, Bagella L. Histone deacetylase inhibitors in the treatment of hematological malignancies and solid tumors. J Biomed Biotechnol. 2011;2011:475641.

    Article  PubMed  Google Scholar 

  71. Shankar S, Srivastava RK. Histone deacetylase inhibitors: mechanisms and clinical significance in cancer: HDAC inhibitor-induced apoptosis. Adv Exp Med Biol. 2008;615:261–98.

    Article  PubMed  CAS  Google Scholar 

  72. Dawson MA, Kouzarides T, Huntly BJ. Targeting epigenetic readers in cancer. N Engl J Med. 2012;367:647–57.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Andrew Emili, Jack Greenblatt, Michael Tyers, John Parkinson, and Zhaolei Zhang as well as members of their teams for many fruitful discussions. We gratefully acknowledge support by the Canadian Institutes of Health Research [MOP#82940], the Ontario Research Fund Global Leadership Program, and the SickKids Foundation. SJW was Canada Research Chair, Tier 1, funded by the Canada Institute of Health Research.

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Authors and Affiliations

  1. Molecular Structure and Function Program, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada, M5G 1X8

    Shuye Pu M.D., M.Sc. & Shoshana Wodak Ph.D.

  2. Research Institute, Molecular Structure and Function Program, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada, M5G 1X8

    Andrei L. Turinsky Ph.D., M.Sc.

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  1. Shuye Pu M.D., M.Sc.
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  2. Andrei L. Turinsky Ph.D., M.Sc.
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  3. Shoshana Wodak Ph.D.
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Correspondence to Shuye Pu M.D., M.Sc. or Shoshana Wodak Ph.D. .

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Editors and Affiliations

  1. Banting & Best Dept. Medical Research, University of Toronto Donnelly Ctr Cell. & Biomolecular Res., Toronto, Ontario, Canada

    Andrew Emili

  2. University of Toronto Terrence Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada

    Jack Greenblatt

  3. Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, Ontario, Canada

    Shoshana Wodak

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Pu, S., Turinsky, A.L., Wodak, S. (2014). Chromatin Biology and Cancer Linked Through Protein–Protein Interactions. In: Emili, A., Greenblatt, J., Wodak, S. (eds) Systems Analysis of Chromatin-Related Protein Complexes in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7931-4_3

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