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DNA Methylation and Histone Modifications in Patients With Cancer

Potential Prognostic and Therapeutic Targets

  • Protocol
Target Discovery and Validation Reviews and Protocols

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 361))

Abstract

Epigenetics, a combination of DNA modifications, chromatin organization, and variations in its associated proteins, configure a new entity that regulates gene expression throughout methylation, acetylation, and chromatin remodeling. In addition to silencing as a result of mutations, loss of heterozygosity, or classical genetic events epigenetic modification symbolizes essential early events during carcinogenesis and tumor development. The reversion of these epigenetic processes restoring normal expression of tumor-suppressor 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 and prognosis.

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References

  1. Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F., and Richmond, T. J. (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251–260.

    Article  CAS  PubMed  Google Scholar 

  2. Strahl, B. D. and Allis, C. D. (2000) The language of covalent histone modifications. Nature 403, 41–45.

    Article  CAS  PubMed  Google Scholar 

  3. Davie, J. K. and Dent, S. Y. (2004) Histone modifications in corepressor functions. Curr. Top. Dev. Biol. 59, 145–163.

    Article  CAS  PubMed  Google Scholar 

  4. Pickart, C. M. (2001) Ubiquitin enters the new millennium. Mol. Cell. 8, 499–504.

    Article  CAS  PubMed  Google Scholar 

  5. Kondo, Y., Shen, L., and Issa, J. P. (2003) Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol. Cell. Biol. 23, 206–215.

    Article  CAS  PubMed  Google Scholar 

  6. Shiio, Y. and Eisenman, R. N. (2003) Histone sumoylation is associated with transcriptional repression. Proc. Natl. Acad. Sci. USA 100, 13,225–13,230.

    Article  CAS  PubMed  Google Scholar 

  7. Rice, J. C. and Allis, C. D. (2001) Code of silence. Nature 414, 258–261.

    Article  CAS  PubMed  Google Scholar 

  8. Yoder, J. A., Soman, N. S., Verdine, G. L., and Bestor, T. H. (1997) DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J. Mol. Biol. 270, 385–395.

    Article  CAS  PubMed  Google Scholar 

  9. Esteller, M., Fraga, M. F., Guo, M., et al. (2001) DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum. Mol. Genet. 10, 3001–3007.

    Article  CAS  PubMed  Google Scholar 

  10. Antequera, F. and Bird, A. (1993) Number of CpG islands and genes in human and mouse. Proc. Natl. Acad. Sci. USA 90, 11,995–11,999.

    Article  CAS  PubMed  Google Scholar 

  11. Bestor, T. H. (2000) The DNA methyltransferases of mammals. Hum. Mol. Genet. 9, 2395–2402.

    Article  CAS  PubMed  Google Scholar 

  12. Bird, A. P. and Wolffe, A. P. (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99, 451–454.

    Article  CAS  PubMed  Google Scholar 

  13. Esteller, M., Corn, P. G., Baylin, S. B., and Herman, J. G. (2001) A gene hypermethylation profile of human cancer. Cancer. Res. 61, 3225–3229.

    CAS  PubMed  Google Scholar 

  14. Paz, M. F., Wei, S., Cigudosa, J. C., et al. (2003) Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. Hum. Mol. Genet. 12, 2209–2219.

    Article  CAS  PubMed  Google Scholar 

  15. Razin, A. (1998) CpG methylation, chromatin structure and gene silencing-a three-way connection. Embo. J. 17, 4905–4908.

    Article  CAS  PubMed  Google Scholar 

  16. Cervoni, N. and Szyf, M. (2001) Demethylase activity is directed by histone acetylation. J. Biol. Chem. 276, 40,778–40,787.

    Article  CAS  PubMed  Google Scholar 

  17. Cervoni, N., Detich, N., Seo, S. B., Chakravarti, D., and Szyf, M. (2002) The oncoprotein Set/TAF-1beta, an inhibitor of histone acetyltransferase, inhibits active demethylation of DNA, integrating DNA methylation and transcriptional silencing. J. Biol. Chem. 277, 25,026–25,031.

    Article  CAS  PubMed  Google Scholar 

  18. Esteller, M., Cordon-Cardo, C., Corn, P. G., et al. (2001) p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2. Cancer Res. 61, 2816–2821.

    CAS  PubMed  Google Scholar 

  19. Plumb, J. A., Strathdee, G., Sludden, J., Kaye, S. B., and Brown, R. (2000) Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 60, 6039–6044.

    CAS  PubMed  Google Scholar 

  20. Esteller, M., Garcia-Foncillas, J., Andion, E., et al. (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343, 1350–1354.

    Article  CAS  PubMed  Google Scholar 

  21. Esteller, M., Gaidano, G., Goodman, S. N., et al. (2002) Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J. Natl. Cancer Inst. 94, 26–32.

    CAS  PubMed  Google Scholar 

  22. Plass, C., Shibata, H., Kalcheva, I., et al. (1996) Identification of Grf1 on mouse chromosome 9 as an imprinted gene by RLGS-M. Nat. Genet. 14, 106–109.

    Article  CAS  PubMed  Google Scholar 

  23. Herman, J. G., Jen, J., Merlo, A., and Baylin, S. B. (1996) Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res. 56, 722–727.

    CAS  PubMed  Google Scholar 

  24. Jones, P. A. and Baylin, S. B. (2002) The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428.

    Article  CAS  PubMed  Google Scholar 

  25. Robertson, K. D. and Jones, P. A. (2000) DNA methylation: past, present and future directions. Carcinogenesis 21, 461–467.

    Article  CAS  PubMed  Google Scholar 

  26. Robertson K. D. and Jones, P. A. (1999) The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol. Cell. Biol. 18, 6457–6473.

    Google Scholar 

  27. Esteller, M., Tortola, S., Toyota, M., et al. (2000) Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res. 60, 129–133.

    CAS  PubMed  Google Scholar 

  28. Esteller, M., Cordon-Cardo, C., Corn, P. G., et al. (2001) P14ARF silencing by promoter hypermethylation mediated abnormal intracellular localization of MDM2. Cancer Res. 61, 2816–2821.

    CAS  PubMed  Google Scholar 

  29. Corn, P. G., Kuerbitz, S. J., Van Noesel, M. M., et al. (1999) Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5′ CpG island methylation. Cancer Res. 59, 3352–3356.

    CAS  PubMed  Google Scholar 

  30. Herman, J. G., Merlo, A., Mao, L. et al. (1995) Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 55, 4525–4530.

    CAS  PubMed  Google Scholar 

  31. Merlo, A., Herman, J. G., Mao, L., et al. (1995) 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat. Med. 1, 686–692.

    Article  CAS  PubMed  Google Scholar 

  32. Gonzalez-Zulueta, M., Bender, C. M., Yang, A. S., et al. (1995) Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 55, 4531–4535.

    CAS  PubMed  Google Scholar 

  33. Greger, V., Passarge, E., Hopping, W., Messmer, E., and Horsthemke, B. (1989) Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum. Genet. 83, 155–158.

    Article  CAS  PubMed  Google Scholar 

  34. Herman, J. G., Jen, J., Merlo, A., and Baylin, S. B. (1996) Hypermethylationassociated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res. 56, 722–727.

    CAS  PubMed  Google Scholar 

  35. Kane, M. F., Loda, M., Gaida, G. M., et al. (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811.

    CAS  PubMed  Google Scholar 

  36. Herman, J. G., Umar, A., Polyak, K., et al. (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl. Acad. Sci. USA 95, 6870–6875.

    Article  CAS  PubMed  Google Scholar 

  37. Esteller, M., Levine, R., Hedrick, L., Ellenson, L. H., and Herman, J. G. (1998) MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinoma. Oncogene 17, 2413–2417.

    Article  CAS  PubMed  Google Scholar 

  38. Esteller, M., Lluis, C., Matias-Guiu, X., et al. (1999) HMLH1 promoter hypermethylation is an early event in endometrial tumorigenesis. Am. J. Pathol. 155, 1767–1772.

    Article  CAS  PubMed  Google Scholar 

  39. Fleisher, A. S., Esteller, M., Wang, S., et al. (1999) Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res. 59, 1090–1095.

    CAS  PubMed  Google Scholar 

  40. Esteller, M., Hamilton, S. R., Burger, P. C., et al. (1999) Inactivation of the DNA repair gene O-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 59, 793–797.

    CAS  PubMed  Google Scholar 

  41. Esteller, M., Toyota, M., Sanchez-Cespedes, M., et al. (2000) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res. 60, 2368–2371.

    CAS  PubMed  Google Scholar 

  42. Esteller, M., Risques, R. A., Toyota, M., et al. (2001) Promoter hypermethylation of the DNA repair gene O-Methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis, Cancer Res. 61, 4689–4692.

    CAS  PubMed  Google Scholar 

  43. Mizuno, K., Osada, H., Konishi, H., et al. (2002) Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers. Oncogene 21, 2328–2333.

    Article  CAS  PubMed  Google Scholar 

  44. Esteller, M., Silva, J. M., Dominguez, G., et al. (2000) Promoter hypermethylation is a cause of BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl. Cancer Inst. 92, 564–569.

    Article  CAS  PubMed  Google Scholar 

  45. Hedelfank, I., Duggan, D., Chen, Y., et al. (2001) Gene-expression profiles in hereditary breast cancer. N. Engl. J. Med. 343, 539–548.

    Google Scholar 

  46. Johnstone, R. W. (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat. Rev. Drug Discov. 1, 287–299.

    Article  CAS  PubMed  Google Scholar 

  47. Jenuwein, T. and Allis, C. D. (2001) Translating the histone code. Science 293, 1074–1080.

    Article  CAS  PubMed  Google Scholar 

  48. Winston, F. and Allis, C. D. (1999) The bromodomain: a chromatin-targeting module? Nat. Struct. Biol. 6, 601–604.

    Article  CAS  PubMed  Google Scholar 

  49. Dhalluin, C., Carlson, J. E., Zeng, L., He, C., Aggarwal, A. K., and Zhou, M. M. (1999) Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496.

    Article  CAS  PubMed  Google Scholar 

  50. Fahrner, J. A., Eguchi, S., Herman, J. G., and Baylin, S. B. (2002) Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res. 62, 7213–7218.

    CAS  PubMed  Google Scholar 

  51. Nguyen, C. T., Weisenberger, D. J., Velicescu, M., et al. (2002) 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. 62, 6456–6461.

    CAS  PubMed  Google Scholar 

  52. Strahl, B. D., Ohba, R., Cook, R. G., and Allis, C. D. (1999) Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc. Natl. Acad. Sci. USA 96, 14,967–14,972.

    Article  CAS  PubMed  Google Scholar 

  53. Schubeler, D., MacAlpine, D. M., Scalzo, D., et al. (2004) The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 18, 1263–1271.

    Article  PubMed  Google Scholar 

  54. Cuthbert, G. L., Daujat, S., Snowden, A. W., et al. (2004). Histone deimination antagonizes arginine methylation. Cell 118, 545–553.

    Article  CAS  PubMed  Google Scholar 

  55. Workman, J. L. and Abmayr, S. M. (2004) Histone H3 variants and modifications on transcribed genes. Proc. Natl. Acad. Sci. USA 101, 1429–1430.

    Article  CAS  PubMed  Google Scholar 

  56. Cao, R. and Zhang, Y. (2004) SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol. Cell 15, 57–67.

    Article  CAS  PubMed  Google Scholar 

  57. Hamamoto, R., Furukawa, Y., Morita, M., et al. (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat. Cell Biol. 6, 731–740.

    Article  CAS  PubMed  Google Scholar 

  58. Fearon, E. R. and Vogelstein, B. (1990) A genetic model for colorectal tumorigenesis. Cell 61, 759–767.

    Article  CAS  PubMed  Google Scholar 

  59. Vogelstein, B. (1990) Cancer. A deadly inheritance. Nature 348, 681–682.

    Article  CAS  PubMed  Google Scholar 

  60. Esteller, M., Corn, P. G., Baylin, S. B., and Herman, J. G. (2001) A gene hypermethylation profile of human cancer. Cancer Res. 61, 3225–3229.

    CAS  PubMed  Google Scholar 

  61. Esteller, M. (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21, 5427–5440.

    Article  CAS  PubMed  Google Scholar 

  62. Fraga, M. F. and Esteller, M. (2002) DNA methylation: a profile of methods and applications. BioTechniques 33, 632–649.

    CAS  PubMed  Google Scholar 

  63. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G., and Baylin, S. B. (1999) Synergy of demethylation and histone deacetylase inhibition in the reexpression of genes silenced in cancer. Nat. Genet. 21, 103–107.

    Article  CAS  PubMed  Google Scholar 

  64. Suzuki, H., Gabrielson, E., Chen, W., et al. (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet. 31, 141–149.

    Article  CAS  PubMed  Google Scholar 

  65. Yamashita, K., Upadhyay, S., Osada, M., et al. (2002) Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell 2, 485–495.

    Article  CAS  PubMed  Google Scholar 

  66. Baylin, S. B. and Herman, J. G. (2001) Promoter hypermethylation—can this change alone ever designate true tumor suppressor gene function? J. Natl. Cancer Inst. 93, 664–665.

    Article  CAS  PubMed  Google Scholar 

  67. Chen, R. Z., Pettersson, U., Beard, C., Jackson-Grusby, L., and Jaenisch, R. (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395, 89–93.

    Article  CAS  PubMed  Google Scholar 

  68. Wijermans, P. W., Krulder, J. W., Huijgens, P. C., and Neve, P. (1997) Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 11, 1–5.

    Article  CAS  PubMed  Google Scholar 

  69. Schwartsmann, G., Fernandes, M. S., Schaan, M. D., et al. (1997) Decitabine (5-Aza-2′-deoxycytidine; DAC) plus daunorubicin as a first line treatment in patients with acute myeloid leukemia: preliminary observations. Leukemia 11, S28–S31.

    PubMed  Google Scholar 

  70. Alaminos, M., Davalos, V., Cheung, N. K., Gerald, W. L., and Esteller, M. (2004) Clustering of gene hypermethylation associated with clinical risk groups in neuroblastoma. J. Natl. Cancer Inst. 96, 1208–1219.

    Article  CAS  PubMed  Google Scholar 

  71. Ahrendt, S. A., Chow, J. T., Xu, L. H., et al. (1999) Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J. Natl. Cancer Inst. 91, 332–339.

    Article  CAS  PubMed  Google Scholar 

  72. Sanchez-Cespedes, M., Esteller, M., Hibi, K., et al. (1999) Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. Clin. Cancer Res. 5, 2450–2454.

    CAS  PubMed  Google Scholar 

  73. Palmisano, W. A., Divine, K. K., Saccomanno, G., et al. (2000) Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res. 60, 5954–5958.

    CAS  PubMed  Google Scholar 

  74. Cairns, P., steller, M., Herman, J. G., et al. (2001) Molecular detection of prostate cancer in urine by GSTP1 hypermethylation. Clin. Cancer Res. 7, 2727–2730.

    CAS  PubMed  Google Scholar 

  75. Goessl, C., Muller, M., and Miller, K. (2000) Methylation-specific PCR (MSP) for detection of tumour DNA in the blood plasma and serum of patients with prostate cancer. Prostate Cancer Prostatic Dis. 3, S17.

    Article  PubMed  Google Scholar 

  76. Evron, E., Dooley, W. C., Umbricht, C. B., et al. (2001) Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR. Lancet 357, 1335–1336.

    Article  CAS  PubMed  Google Scholar 

  77. Rosas, S. L., Koch, W., da Costa Carvalho, M. G., et al. (2001) Promoter hypermethylation patterns of p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase in tumors and saliva of head and neck cancer patients. Cancer Res. 61, 939–942.

    CAS  PubMed  Google Scholar 

  78. Esteller, M., Sanchez-Cespedes, M., Rosell, R., Sidransky, D., Baylin, S. B., and Herman, J. G. (1999) Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res. 59, 67–70.

    CAS  PubMed  Google Scholar 

  79. Kawakami, K., Brabender, J., Lord, R. V., et al. (2000) Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J. Natl. Cancer Inst. 92, 1805–1811.

    Article  CAS  PubMed  Google Scholar 

  80. Grady, W. M., Rajput, A., Lutterbaugh, J. D., and Markowitz, S. D. (2001) Detection of aberrantly methylated hMLH1 promoter DNA in the serum of patients with microsatellite unstable colon cancer. Cancer Res. 61, 900–902.

    CAS  PubMed  Google Scholar 

  81. Esteller, M. and Herman, J. G. (2004) Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer. Oncogene 23, 1–8.

    Article  CAS  PubMed  Google Scholar 

  82. Ottaviano, Y. L., Issa, J. P., Parl, F. F., Smith, H. S., Baylin, S. B., and Davidson, N. E. (1994) Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res. 54, 2552–2555.

    CAS  PubMed  Google Scholar 

  83. Ballestar, E. and Esteller, M. (2002) The impact of chromatin in human cancer: linking DNA methylation to gene silencing. Carcinogenesis 23, 1103–1109.

    Article  CAS  PubMed  Google Scholar 

  84. Fraga, M. F., Uriol, E., and Diego, L. B., et al. (2002) High performance capillary electrophoretic method for the quantification of 5-methyl 2′-deoxycytidine in genomic DNA: application to plant, animal and human cancer tissues. Electrophoresis 23, 1677–1681.

    Article  CAS  PubMed  Google Scholar 

  85. Paz, M. F., Fraga, M. F., Avila, S., et al. (2003) A systematic profile of DNA methylation in human cancer cell lines. Cancer Res. 63, 1114–1121.

    CAS  PubMed  Google Scholar 

  86. Daskalakis, M., Nguyen, T. T., Nguyen, C., et al. (2002) Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 100, 2957–2964.

    Article  CAS  PubMed  Google Scholar 

  87. Christman, J. K. (2002) 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21, 5483–5495.

    Article  CAS  PubMed  Google Scholar 

  88. Lo Coco, F., Zelent, A., Kimchi, A., et al. (2002) Progress in differentiation induction as a treatment for acute promyelocytic leukemia and beyond. Cancer Res. 62, 5618–5621.

    PubMed  Google Scholar 

  89. Soengas, M. S., Capodieci, P., Polsky, D., et al. (2001) Inactivation of the apoptosis effector Apaf-1 in melanoma. Nature 409, 207–211.

    Article  CAS  PubMed  Google Scholar 

  90. Spotswood, H. T. and Turner, B. M. (2002) An increasingly complex code. J. Clin. Invest. 110, 577–582.

    CAS  PubMed  Google Scholar 

  91. Peterson, C. L. and Laniel, M. A. (2004) Histones and histone modifications. Curr. Biol. 14, R546–R551.

    Article  CAS  PubMed  Google Scholar 

  92. Hake, S. B., Xiao, A., and Allis, C. D. (2004) Linking the epigenetic ‘language’ of covalent histone modifications to cancer. Br. J. Cancer 90, 761–769.

    Article  CAS  PubMed  Google Scholar 

  93. Hubbert, C., Guardiola, A., Shao, R., et al. (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458.

    Article  CAS  PubMed  Google Scholar 

  94. Marks, P. A., Miller, T., and Richon, V. M. (2003) Histone deacetylases. Curr. Opin. Pharmacol. 3, 344–351.

    Article  CAS  PubMed  Google Scholar 

  95. de Ruijter, A. J., van Gennip, A. H., Caron, H. N., Kemp, S., and van Kuilenburg, A. B. (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 370, 737–749.

    Article  PubMed  Google Scholar 

  96. Marks, P., Rifkind, R. A., Richon, V. M., Breslow, R., Miller, T., and Kelly, W. K. (2001) Histone deacetylases and cancer: causes and therapies. Nat. Rev. Cancer 1, 194–202.

    Article  CAS  PubMed  Google Scholar 

  97. Deckert, J. and Struhl, K. (2001) Histone acetylation at promoters is differentially affected by specific activators and repressors. Mol. Cell. Biol. 21, 2726–2735.

    Article  CAS  PubMed  Google Scholar 

  98. Butler, L. M., Zhou, X., Xu, W. S., et al. (2002) The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc. Natl. Acad. Sci. USA 99, 11,700–11,705.

    Article  CAS  PubMed  Google Scholar 

  99. Dehm, S. M., Hilton, T. L., Wang, E. H., and Bonham, K. (2004) SRC proximal and core promoter elements dictate TAF1 dependence and transcriptional repression by histone deacetylase inhibitors. Mol. Cell. Biol. 24, 2296–2307.

    Article  CAS  PubMed  Google Scholar 

  100. Hirsch, C. L. and Bonham, K. (2004) Histone deacetylase inhibitors regulate p21WAF1 gene expression at the post-transcriptional level in HepG2 cells. FEBS Lett. 570, 37–40.

    Article  CAS  PubMed  Google Scholar 

  101. Yoshida, M., Kijima, M., Akita, M., and Beppu, T. (1990) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265, 17,174–17,179.

    CAS  PubMed  Google Scholar 

  102. Remiszewski, S. W., Sambucetti, L. C., Bair, K. W., et al. (2003) N-Hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity: discovery of (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824). J. Med. Chem. 46, 4609–4624.

    Article  CAS  PubMed  Google Scholar 

  103. Atadja, P., Gao, L., Kwon, P., et al. (2004) Selective growth inhibition of tumor cells by a novel histone deacetylase inhibitor, NVP-LAQ824. Cancer Res. 64, 689–695.

    Article  CAS  PubMed  Google Scholar 

  104. Plumb, J. A., Finn, P. W., Williams, R. J., et al. (2003) Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol. Cancer Ther. 2, 721–728.

    CAS  PubMed  Google Scholar 

  105. Sealy, L. and Chalkley, R. (1978) The effect of sodium butyrate on histone modification. Cell 14, 115–121.

    Article  CAS  PubMed  Google Scholar 

  106. Phiel, C. J., Zhang, F., Huang, E. Y., Guenther, M. G., Lazar, M. A., and Klein, P. S. (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem. 276, 36,734–36,741.

    Article  CAS  PubMed  Google Scholar 

  107. Gottlicher, M., Minucci, S., Zhu, P., et al. (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969–6978.

    Article  CAS  PubMed  Google Scholar 

  108. Lea, M. A. and Tulsyan, N. (1995) Discordant effects of butyrate analogues on erythroleukemia cell proliferation, differentiation and histone deacetylase. Anticancer Res. 15, 879–883.

    CAS  PubMed  Google Scholar 

  109. Gore, S. D., Weng, L. J., Figg, W. D., et al. (2002) Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin. Cancer Res. 8, 963–970.

    CAS  PubMed  Google Scholar 

  110. Patnaik, A., Rowinsky, E. K., Villalona, M. A., et al. (2002) A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies. Clin. Cancer Res. 8, 2142–2148.

    CAS  PubMed  Google Scholar 

  111. Saito, A., Yamashita, T., Mariko, Y., et al. (1999) A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc. Natl. Acad. Sci. USA 96, 4592–4597.

    Article  CAS  PubMed  Google Scholar 

  112. Fournel, M., Trachy-Bourget, M. C., Yan, P. T., et al. (2002) Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors. Cancer Res. 62, 4325–4330.

    CAS  PubMed  Google Scholar 

  113. Kraker, A. J., Mizzen, C. A., Hartl, B. G., Miin, J., Allis, C. D., and Merriman, R. L. (2003) Modulation of histone acetylation by [4-(acetylamino)-N-(2-aminophenyl) benzamide] in HCT-8 colon carcinoma. Mol. Cancer Ther. 2, 401–408.

    CAS  PubMed  Google Scholar 

  114. Furumai, R., Komatsu, Y., Nishino, N., Khochbin, S., Yoshida, M., and Horinouchi, S. (2001) Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proc. Natl. Acad. Sci. USA 98, 87–92.

    Article  CAS  PubMed  Google Scholar 

  115. Darkin-Rattray, S. J., Gurnett, A. M., Myers, R. W., et al. (1996) Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc. Natl. Acad. Sci. USA 93, 13,143–13,147.

    Article  CAS  PubMed  Google Scholar 

  116. Murphy, J. P., McAleer, J. P., Uglialoro, A., et al. (2000) Histone deacetylase inhibitors and cell proliferation in pea root meristems. Phytochemistry 55, 11–18.

    Article  CAS  PubMed  Google Scholar 

  117. Murray, P. J., Kranz, M., Ladlow, M., et al. (2001) The synthesis of cyclic tetrapeptoid analogues of the antiprotozoal natural product apicidin. Bioorg. Med. Chem. Lett. 11, 773–776.

    Article  CAS  Google Scholar 

  118. Hong, J., Ishihara, K., Yamaki, K., et al. (2003) Apicidin, a histone deacetylase inhibitor, induces differentiation of HL-60 cells. Cancer Lett. 189, 197–206.

    Article  CAS  PubMed  Google Scholar 

  119. Mei, S., Ho, A. D., and Mahlknecht, U. (2004) Role of histone deacetylase inhibitors in the treatment of cancer (Review). Int. J. Oncol. 25, 1509–1519.

    CAS  PubMed  Google Scholar 

  120. Espino, P. S., Drobic, B., Dunn, K. L., and Davie, J. R. (2005) Histone modifications as a platform for cancer therapy. J. Cell. Biochem. 94, 1088–1102.

    Article  CAS  PubMed  Google Scholar 

  121. Guasconi, V. and Ait-Si-Ali, S. (2004) Chromatin dynamics and cancer. Cancer Biol. Ther. 3, 825–830.

    Article  CAS  PubMed  Google Scholar 

  122. Rouaux, C., Loeffler, J. P., and Boutillier, A. L. (2004) Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders. Biochem. Pharmacol. 68, 1157–1164.

    Article  CAS  PubMed  Google Scholar 

  123. Herman, J. G., Graff, J. R., Myohanen, S., Nelkin, B. D., and Baylin, S. B. (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl. Acad. Sci. USA 93, 9821–9826.

    Article  CAS  PubMed  Google Scholar 

  124. Esteller, M., Fraga, M. F., Guo, M., et al. (2001) DNA methylation patterns in hereditary human cancer mimics sporadic tumorigenesis. Hum. Mol. Genet. 10, 3001–3007.

    Article  CAS  PubMed  Google Scholar 

  125. Herman, J. G., Umar, A., Polyak, K., et al. (1998) Incidence and functional consequences of hMLH1promoter hypermethylation in colorectal carcinoma. Proc. Natl. Acad. Sci. USA 95, 6870–6875.

    Article  CAS  PubMed  Google Scholar 

  126. Esteller, M., Levine, R., Baylin, S. B., Ellenson, L. H., and Herman, J. G. (1998) MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 17, 2413–2417.

    Article  CAS  PubMed  Google Scholar 

  127. Esteller, M., Hamilton, S. R., Burger, P. C., Baylin, S. B., and Herman, J. G. (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 59, 793–797.

    CAS  PubMed  Google Scholar 

  128. Hedenfalk, I., Duggan, D., Chen, Y., et al. (2001) Gene-expression profiles in hereditary breast cancer. N. Engl. J. Med. 344, 539–548.

    Article  CAS  PubMed  Google Scholar 

  129. Myohanen, S. K., Baylin, S. B., and Herman, J. G. (1998) Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia. Cancer Res. 58, 591–593.

    CAS  PubMed  Google Scholar 

  130. Yeager, T. R., DeVries, S., Jarrard, D. F., et al. (1998) Overcoming cellular senescence in human cancer pathogenesis. Genes Dev. 12, 163–174.

    Article  CAS  PubMed  Google Scholar 

  131. Esteller, M., Sparks, A., Toyota, M., et al. (2000) Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res. 60, 4366–4371.

    CAS  PubMed  Google Scholar 

  132. Cote, S. and Momparler, R. L. (1997) Activation of the retinoic acid receptor beta gene by 5-aza-2′-deoxycytidine in human DLD-1 colon carcinoma cells. Anticancer Drugs 8, 56–61.

    Article  CAS  PubMed  Google Scholar 

  133. Virmani, A. K., Rathi, A., Zochbauer-Muller, S., et al. (2000) Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. J. Natl. Cancer Inst. 92, 1303–1307.

    Article  CAS  PubMed  Google Scholar 

  134. Esteller, M., Guo, M., Moreno, V., et al. (2002) Hypermethylation-associated inactivation of the cellular retinol-binding-protein 1 gene in human cancer. Cancer Res. 62, 5902–5905.

    CAS  PubMed  Google Scholar 

  135. Villar-Garea, A. and Esteller, M. (2003) DNA demethylating agents and chromatin-remodelling drugs: which, how and why? Curr. Drug Metab. 4, 11–31.

    Article  CAS  PubMed  Google Scholar 

  136. Cheng, J. C., Matsen, C. B., Gonzales, F. A., et al. (2003) Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J. Natl. Cancer Inst. 95, 399–409.

    Article  CAS  PubMed  Google Scholar 

  137. Cheng, J. C., Yoo, C. B., Weisenberger, D. J., et al. (2004) Preferential response of cancer cells to zebularine. Cancer Cell 6, 151–158.

    Article  CAS  PubMed  Google Scholar 

  138. Lin, X., Asgari, K., Putzi, M. J., et al. (2001) 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. 61, 8611–8616.

    CAS  PubMed  Google Scholar 

  139. Villar-Garea, A., Fraga, M. F., Espada, J., and Esteller, M. (2003) Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res. 63, 4984–4989.

    CAS  PubMed  Google Scholar 

  140. Pinto, A., Zagonel, V., Attadia, V., et al. (1989) 5-Aza-2-deoxycytidine as a differentiation inducer in acute myeloid leukaemias and myelodysplastic syndromes of the elderly. Bone Marrow Transplant 4, 28–32.

    PubMed  Google Scholar 

  141. Silverman, L. R., Holland, J. F., Weinberg, R. S., et al. (1993) Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia 7, 21–29.

    PubMed  Google Scholar 

  142. Silverman, L. R., Demakos, E. P., Peterson, B. L., et al. (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol. 20, 2429–2440.

    Article  CAS  PubMed  Google Scholar 

  143. Turner, B. M. (2002) Cellular memory and the histone code. Cell 111, 285–291.

    Article  CAS  PubMed  Google Scholar 

  144. Bannister, A. J. and Kouzarides, T. (2004) Histone methylation: recognizing the methyl mark. Methods Enzymol. 376, 269–288.

    Article  CAS  PubMed  Google Scholar 

  145. Ng, H. H., Zhang, Y., Hendrich, B., et al. (1999) MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genet. 23, 58–61.

    CAS  PubMed  Google Scholar 

  146. Wade, P. A., Gegonne, A., Jones, P. L., Ballestar, E., Aubry, F., and Wolffe, A. P. (1999) Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23, 62–66.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Cancer Epigenetic Laboratory, Molecular Pathology Program, Spanish National Canter Centre, Madrid, Spain

    Michel Herranz & Manel Esteller

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  1. Michel Herranz
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  2. Manel Esteller
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  1. Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway

    Mouldy Sioud

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Herranz, M., Esteller, M. (2007). DNA Methylation and Histone Modifications in Patients With Cancer. In: Sioud, M. (eds) Target Discovery and Validation Reviews and Protocols. Methods in Molecular Biology™, vol 361. Humana Press. https://doi.org/10.1385/1-59745-208-4:25

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  • DOI: https://doi.org/10.1385/1-59745-208-4:25

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-890-4

  • Online ISBN: 978-1-59745-208-3

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