Clinical & Translational Oncology

, Volume 8, Issue 4, pp 242–249 | Cite as

New therapeutic targets in cancer: the epigenetic connection

  • Michel Herranz
  • Manel EstellerEmail author
Educational Series Green Series


Cancer is an epigenetic disease, a combination of DNA modifications, chromatin organization and variations in its associated proteins, configure a new entity that regulates gene function throughout methylation, acetylation and chromatin remodelling. Irregularde novo DNA methylation, mainly promoter hypermethylation, histone deacetylation or methylation are important means for the transcriptional repression of cancer-associated genes. Reverse these epigenetic processes restoring normal expression of malignancy-preventing-genes has consequently become a new therapeutic target in cancer treatment. Aberrant patterns of epigenetic modifications will be, in a near future, crucial parameters in cancer diagnosis, prognosis and therapy.

Key words

cancer epigenetics histone modifications DNA methylation prognosis therapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000; 403:41–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Davie JK, Dent SY. Histone modifications in corepressor functions. Curr Top Dev Biol. 2004;59:145–63.PubMedCrossRefGoogle Scholar
  3. 3.
    Pickart CM. Ubiquitin enters the new millennium. Mol Cell. 2001;8:499–504.PubMedCrossRefGoogle Scholar
  4. 4.
    Kondo Y, Shen L, Issa JP. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol. 2003;23:206–15.PubMedCrossRefGoogle Scholar
  5. 5.
    Shiio Y, Eisenman RN. Histone sumoylation is associated with transcriptional repression. Proc Natl Acad Sci USA. 2003; 100:13225–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Yoder JA, Soman NS, Verdine GL, Bestor TH. DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J Mol Biol. 1997; 270:385–95.PubMedCrossRefGoogle Scholar
  7. 7.
    Esteller M, Fraga MF, Guo M, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet. 2001;10:3001–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res. 2001;61:3225–9.PubMedGoogle Scholar
  9. 9.
    Paz MF, Wei S, Cigudosa JC, et al. Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. Hum Mol Genet. 2003;12:2209–19.PubMedCrossRefGoogle Scholar
  10. 10.
    Razin, A. CpG methylation, chromatin structure and gene silencing-a three-way connection. Embo J. 1998;17:4905–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Plass C, Shibata H, Kalcheva I, et al. Identification of Grfl on mouse chromosome 9 as an imprinted gene by RLGS-M. Nat Genet. 1996;14:106–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Robertson KD, Jones PA. DNA methylation: past, present and future directions. Carcinogenesis. 2000;21:461–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Jenuwein, T., Allis CD. Translating the histone code. Science. 2001;293:1074–80.PubMedCrossRefGoogle Scholar
  14. 14.
    Winston F, Allis CD. The bromodomain: a chromatin-targeting module? Nat Struct Biol. 1999;6:601–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM. Structure and ligand of a histone acetyltransferase bromodomain. Nature. 1999;399:491–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Fahrner JA, Eguchi S, Herman JG, Baylin SB. Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res. 2002; 62:7213–8.PubMedGoogle Scholar
  17. 17.
    Nguyen CT, Weisenberger DJ, Velicescu M, et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res. 2002;62: 6456–61.PubMedGoogle Scholar
  18. 18.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61: 759–67.PubMedCrossRefGoogle Scholar
  19. 19.
    Vogelstein B. Cancer. A deadly inheritance. Nature. 1990;348:681–2.PubMedCrossRefGoogle Scholar
  20. 20.
    Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21: 103–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Suzuki H, Gabrielson E, Chen W, et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet. 2002;31:141–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Wijermans PW, Krulder JW, Huijgens PC, Neve P Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia. 1997;11:1–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Soengas MS, Capodieci P, Polsky D, et al., Inactivation of the apoptosis effector Apaf-1 in melanoma, Nature. 2001;409:207–11.PubMedCrossRefGoogle Scholar
  24. 24.
    Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1:194–202.PubMedCrossRefGoogle Scholar
  25. 25.
    Deckert J, Struhl K. Histone acetylation at promoters is differentially affected by specific activators and repressors. Mol Cell Biol. 2001;21:2726–35.PubMedCrossRefGoogle Scholar
  26. 26.
    Villar-Garea A, Esteller M. DNA demethylating agents and chromatin-remodelling drugs: which, how and why? Curr Drug Metab. 2003;4:11–31.PubMedCrossRefGoogle Scholar
  27. 27.
    Cheng JC, Matsen CB, Gonzales FA, et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst. 2003;95:399–409.PubMedCrossRefGoogle Scholar
  28. 28.
    Cheng JC, Yoo CB, Weisenberger DJ, et al. Preferential response of cancer cells to zebularine. Cancer Cell. 2004;6:151–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Lin X, Asgari K, Putzi MJ, et al. Reversal of GSTP1 CpG island hypermethylation and reactivation of pi-class glutathione S-transferase (GSTP1) expression in human prostate cancer cells by treatment with procainamide. Cancer Res. 2001;61:8611–6.PubMedGoogle Scholar
  30. 30.
    Villar-Garea A, Fraga MF, Espada J, Esteller M. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res. 2003;63:4984–9.PubMedGoogle Scholar
  31. 31.
    Pinto A, Zagonel V, Attadia V, et al. 5-Aza-2-deoxycytidine as a differentiation inducer in acute myeloid leukaemias and myelodysplastic syndromes of the elderly. Bone Marrow Transplant. 1989;4 Suppl 3: S28–32.Google Scholar
  32. 32.
    Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20: 2429–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Turner BM. Cellular memory and the histone code. Cell. 2002;111:285–91.PubMedCrossRefGoogle Scholar

Copyright information

© FESEO 2006

Authors and Affiliations

  1. 1.Cancer Epigenetics Laboratory. Molecular Pathology ProgramSpanish National Cancer Center (CNIO)MadridSpain

Personalised recommendations