Skip to main content

Prospects for Epigenetic Compounds in the Treatment of Autoimmune Disease

  • Chapter
Epigenetic Contributions in Autoimmune Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 711))

Abstract

There is growing evidence for a role for epigenetic mechanisms in the development of autoimmune diseases. In most cases of autoimmune disease the precise epigenetic mechanism involved remains to be resolved, however DNA hypomethylation accompanied by hypoacetylation of histone H3/H4 is commonly observed. Due to the reversible nature of epigenetic marks their maintenance enzymes such as DNA methyltransferases (DNMTs), histone deacetylases (HDACs) and histone lysine methyltransferases (HKMT) are attractive drug targets. Small molecule inhibitors of histone modification and DNA methylation maintenance are increasingly becoming available and will be useful chemical biological tools to dissect epigenetic mechanisms in these diseases. However, although epigenetic therapies used in cancer treatment are a promising starting point for the exploration of autoimmune disease treatment, there is a requirement for more specific and less toxic agents for these chronic diseases or for use as chemopreventative agents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Hernick M, Fierke CA. Zinc hydrolases: the mechanisms of zinc-dependent deacetylases. Arch Biochem Biophys 2005; 433(1):71–84.

    Article  PubMed  CAS  Google Scholar 

  2. de Ruijter AJ, van Gennip AH, Caron HN et al. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003; 370(Pt 3):737–749.

    Article  PubMed  Google Scholar 

  3. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5(9):769–784.

    Article  PubMed  CAS  Google Scholar 

  4. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 2007; 26(37):5541–5552.

    Article  PubMed  CAS  Google Scholar 

  5. Warrener R, Beamish H, Burgess A et al. Tumor cell-selective cytotoxicity by targeting cell cycle checkpoints. FASEB J 2003; 17(11):1550–1552.

    PubMed  CAS  Google Scholar 

  6. Gui CY, Ngo L, Xu WS et al. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA 2004; 101(5):1241–1246.

    Article  PubMed  CAS  Google Scholar 

  7. Blanchard F, Chipoy C. Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases? Drug Discov Today 2005; 10(3):197–204.

    Article  PubMed  CAS  Google Scholar 

  8. Shuttleworth S, Kerry S. HDAC Inhibitors: New Promise in the Treatment of Immune and Inflammatory Disease. Innovations in Pharmaceutical Technology 2009:16–20.

    Google Scholar 

  9. Yamaguchi H, Woods NT, Piluso LG et al. p53 acetylation is crucial for its transcription-independent proapoptotic functions. J Biol Chem 2009; 284(17):11171–11183.

    Article  PubMed  CAS  Google Scholar 

  10. Bi G, Jiang G. The molecular mechanism of HDAC inhibitors in anticancer effects. Cell Mol Immunol 2006; 3(4):285–290.

    PubMed  CAS  Google Scholar 

  11. Yuan ZL, Guan YJ, Chatterjee D et al. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 2005; 307(5707):269–273.

    Article  PubMed  CAS  Google Scholar 

  12. Chen Lf, Fischle W, Verdin E et al. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 2001; 293(5535):1653–1657.

    Article  CAS  Google Scholar 

  13. Gu W, Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997; 90(4):595–606.

    Article  PubMed  CAS  Google Scholar 

  14. Martinez-Balbas MA et al. Regulation of E2F1 activity by acetylation. EMBO J 2000; 19(4):662–671.

    Article  PubMed  CAS  Google Scholar 

  15. Luo J, Su F, Chen D et al. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 2000; 408(6810):377–381.

    Article  PubMed  CAS  Google Scholar 

  16. Pediconi N, Ianari A, Costanzo A et al. Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nat Cell Biol 2003; 5(6):552–558.

    Article  PubMed  CAS  Google Scholar 

  17. Bandyopadhyay D, Mishra A, Medrano EE. Overexpression of histone deacetylase 1 confers resistance to sodium butyrate-mediated apoptosis in melanoma cells through a p53-mediated pathway. Cancer Res 2004; 64(21):7706–7710.

    Article  PubMed  CAS  Google Scholar 

  18. Haggarty SJ, Koeller KM, Wong JC et al. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA 2003; 100(8):4389–4394.

    Article  PubMed  CAS  Google Scholar 

  19. Backdahl L, Bushell A, Beck S. Inflammatory signalling as mediator of epigenetic modulation in tissue-specific chronic inflammation. Int J Biochem Cell Biol 2009; 41(1):176–184.

    Article  PubMed  CAS  Google Scholar 

  20. Choo QY, Ho PC, Lin HS. Histone deacetylase inhibitors: new hope for rheumatoid arthritis? Curr Pharm Des 2008; 14(8):803–820.

    Article  PubMed  CAS  Google Scholar 

  21. Chabane N, Zayed N, Afif H et al. Histone deacetylase inhibitors suppress interleukin-1beta-induced nitric oxide and prostaglandin E2 production in human chondrocytes. Osteoarthritis Cartilage 2008; 16(10):1267–1274.

    Article  PubMed  CAS  Google Scholar 

  22. Mahmoodi M, Sahebjam S, Smookler D et al. Lack of tissue inhibitor of metalloproteinases-3 results in an enhanced inflammatory response in antigen-induced arthritis. Am J Pathol 2005; 166(6):1733–1740.

    Article  PubMed  CAS  Google Scholar 

  23. Chung YL, Lee MY, Wang AJ et al. A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. Mol Ther 2003; 8(5):707–717.

    Article  PubMed  CAS  Google Scholar 

  24. Jüngel A, Baresova V, Ospelt C et al. Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann Rheum Dis 2006; 65(7):910–912.

    Article  PubMed  Google Scholar 

  25. Nakamura C, Matsushita I, Kosaka E et al. Anti-arthritic effects of combined treatment with histone deacetylase inhibitor and low-intensity ultrasound in the presence of microbubbles in human rheumatoid synovial cells. Rheumatology (Oxford) 2008; 47(4):418–424.

    Article  CAS  Google Scholar 

  26. Lin HS, Hu CY, Chan HY et al. Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol 2007; 150(7):862–872.

    Article  PubMed  CAS  Google Scholar 

  27. Nishida K, Komiyama T, Miyazawa S et al. Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 2004; 50(10):3365–3376.

    Article  PubMed  CAS  Google Scholar 

  28. Manabe H, Nasu Y, Komiyama T et al. Inhibition of histone deacetylase down-regulates the expression of hypoxia-induced vascular endothelial growth factor by rheumatoid synovial fibroblasts. Inflamm Res 2008; 57(1):4–10.

    Article  PubMed  CAS  Google Scholar 

  29. Leoni F, Fossati G, Lewis EC et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med 2005; 11(1–12):1–15.

    Article  PubMed  CAS  Google Scholar 

  30. Lührs H, Gerke T, Müller JG et al. Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis. Scand J Gastroenterol 2002; 37(4):458–466.

    Article  PubMed  Google Scholar 

  31. Vernia P, Annese V, Bresci G et al. Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial. Eur J Clin Invest 2003; 33(3):244–248.

    Article  PubMed  CAS  Google Scholar 

  32. Glauben R, Batra A, Fedke I et al. Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 2006; 176(8):5015–5022.

    PubMed  CAS  Google Scholar 

  33. Mishra N, Reilly CM, Brown DR et al. Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J Clin Invest 2003; 111(4):539–552.

    PubMed  CAS  Google Scholar 

  34. Camelo S, Iglesias AH, Hwang D et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 2005; 164(1–2):10–21.

    Article  PubMed  CAS  Google Scholar 

  35. Gray SG, Dangond F. Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis. Epigenetics. 2006; 1(2):67–75.

    Article  PubMed  Google Scholar 

  36. Tovar-Castillo LE, Cancino-Díaz JC, García-Vázquez F et al. Under-expression of VHL and over-expression of HDAC-1, HIF-1alpha, LL-37 and IAP-2 in affected skin biopsies of patients with psoriasis. Int J Dermatol. 2007; 46(3):239–246.

    Article  PubMed  CAS  Google Scholar 

  37. Dhir M, Montgomery EA, Glöckner SC et al. Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia. J Gastrointest Surg 2008; 12(10):1745–1753.

    Article  PubMed  Google Scholar 

  38. Lyko F, Brown R. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst 2005; 97(20):1498–1506.

    Article  PubMed  CAS  Google Scholar 

  39. Santi DV, Norment A, Garrett CE. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc Natl Acad Sci USA 1984; 81(22):6993–6997.

    Article  PubMed  CAS  Google Scholar 

  40. Baylin SB. DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2005; 2Suppl 1:S4–11.

    Article  PubMed  CAS  Google Scholar 

  41. Yoo CB, Jeong S, Egger G et al. Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 2007; 67(13):6400–6408.

    Article  PubMed  CAS  Google Scholar 

  42. Brueckner B, Kuck D, Lyko F. DNA methyltransferase inhibitors for cancer therapy. Cancer J 2007; 13(1):17–22.

    Article  PubMed  CAS  Google Scholar 

  43. Plummer R, Vidal L, Griffin M et al. Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors. Clin Cancer Res 2009; 15(9):3177–3183.

    Article  PubMed  CAS  Google Scholar 

  44. Klisovic RB, Stock W, Cataland S et al. A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia. Clin Cancer Res 2008; 14(8):2444–2449.

    Article  PubMed  CAS  Google Scholar 

  45. Graham JS, Kaye SB, Brown R. The promises and pitfalls of epigenetic therapies in solid tumours. Eur J Cancer 2009; 45(7):1129–1136.

    Article  PubMed  CAS  Google Scholar 

  46. IARC. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. International Agency for Research on Cancer 1990; 50:415.

    Google Scholar 

  47. Jorgensen HF, Bird A. MeCP2 and other methyl-CpG binding proteins. Ment Retard Dev Disabil Res Rev 2002; 8(2):87–93.

    Article  PubMed  Google Scholar 

  48. Unoki M, Kelly JD, Neal DE et al. UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer. Br J Cancer 2009; 101(1):98–105.

    Article  PubMed  CAS  Google Scholar 

  49. Unoki M, Brunet J, Mousli M. Drug discovery targeting epigenetic codes: The great potential of UHRF1, which links DNA methylation and histone modifications, as a drug target in cancers and toxoplasmosis. Biochem Pharmacol 2009; 15:78(10):1279–1288.

    Article  PubMed  CAS  Google Scholar 

  50. Luo Y, Li Y, Su Y et al. Abnormal DNA methylation in T-cells from patients with subacute cutaneous lupus erythematosus. Br J Dermatol 2008; 159(4):827–833.

    Article  PubMed  CAS  Google Scholar 

  51. Richardson B, Scheinbart L, Strahler J et al. Evidence for impaired T-cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 1990; 33(11):1665–1673.

    Article  PubMed  CAS  Google Scholar 

  52. Zhu JK. Active DNA demethylation mediated by DNA glycosylases. Annu Rev Genet 2009; 43:143–166.

    Article  PubMed  CAS  Google Scholar 

  53. Zhu B, Zheng Y, Angliker H et al. 5-Methylcytosine DNA glycosylase activity is also present in the human MBD4 (G/T mismatch glycosylase) and in a related avian sequence. Nucleic Acids Res 2000; 28(21):4157–4165.

    Article  PubMed  CAS  Google Scholar 

  54. Millar CB, Guy J, Sansom OJ et al. Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 2002; 297(5580):403–405.

    Article  PubMed  CAS  Google Scholar 

  55. Wong E, Yang K, Kuraguchi M et al. Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation. Proc Natl Acad Sci USA 2002; 99(23):14937–14942.

    Article  PubMed  CAS  Google Scholar 

  56. Bhattacharya SK, Ramchandani S, Cervoni N et al. A mammalian protein with specific demethylase activity for mCpG DNA. Nature 1999; 397(6720):579–583.

    Article  PubMed  CAS  Google Scholar 

  57. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002; 16(1):6–21.

    Article  PubMed  CAS  Google Scholar 

  58. Balada E, Ordi-Ros J, Serrano-Acedo S et al. Transcript overexpression of the MBD2 and MBD4 genes in CD4+ T-cells from systemic lupus erythematosus patients. J Leukoc Biol 2007; 81(6):1609–1616.

    Article  PubMed  CAS  Google Scholar 

  59. Lei W, Luo Y, Lei W et al. Abnormal DNA methylation in CD4+ T-cells from patients with systemic lupus erythematosus, systemic sclerosis and dermatomyositis. Scand J Rheumatol 2009:1–6.

    Google Scholar 

  60. Brown SE, Suderman MJ, Hallett M et al. DNA demethylation induced by the methyl-CpG-binding domain protein MBD3. Gene 2008; 420(2):99–106.

    Article  PubMed  CAS  Google Scholar 

  61. Morgan HD, Dean W, Coker HA et al. Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 2004; 279(50):52353–52360.

    Article  PubMed  CAS  Google Scholar 

  62. Métivier R, Gallais R, Tiffoche C et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 2008; 452(7183):45–50.

    Article  PubMed  Google Scholar 

  63. Tahiliani M, Koh KP, Shen Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324(5929):930–935.

    Article  PubMed  CAS  Google Scholar 

  64. Bakker J, Lin X, Nelson WG. Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells. J Biol Chem 2002; 277(25):22573–22580.

    Article  PubMed  CAS  Google Scholar 

  65. Auriol E, Billard LM, Magdinier F et al. Specific binding of the methyl binding domain protein 2 at the BRCA1-NBR2 locus. Nucleic Acids Res 2005; 33(13):4243–4254.

    Article  PubMed  CAS  Google Scholar 

  66. Berger J, Bird A. Role of MBD2 in gene regulation and tumorigenesis. Biochem Soc Trans 2005; 33(Pt 6):1537–1540.

    PubMed  CAS  Google Scholar 

  67. Chapman-Rothe N, Brown R. Approaches to target the genome and its epigenome in cancer. Future Med Chem 2009; 1(8):1481–1495.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Chapman-Rothe, N., Brown, R. (2011). Prospects for Epigenetic Compounds in the Treatment of Autoimmune Disease. In: Ballestar, E. (eds) Epigenetic Contributions in Autoimmune Disease. Advances in Experimental Medicine and Biology, vol 711. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8216-2_11

Download citation

Publish with us

Policies and ethics