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>Revistas >Gaceta Médica de México >Año 2002, No. 6

Arenas-Huertero F, Recillas-Targa F
Modificaciones epigenéticas de la cromatina en la generación de cáncer
Gac Med Mex 2002; 138 (6)

Idioma: Español
Referencias bibliográficas: 59
Paginas: 547-555
Archivo PDF: 359.36 Kb.

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Hoy en día, la cromatina representa más que una estructura teñida diferencialmente en el núcleo. Es un nivel de organización que permite regular muchos genes a lo largo del ciclo de vida de los organismos eucariontes. Puede utilizar diferentes modificaciones epigenéticas como: metilación del DNA, acetilación/desacetilación y metilación de histonas así como la participación de los complejos de remodelación SWI/SNF. Algunas enfermedades tienen su origen en las alteraciones de algún componente que participa en organizar y/o modificar la cromatina: las enfermedades neoplásicas no son la excepción. La inactivación de promotores de genes supresores de tumor por metilación del DNA puede iniciar el evento neoplásico. La alteración del balance de la acetilación/desacetilación es uno de los eventos dominantes en algunas leucemias y es casi exclusivo para iniciar el fenotipo leucémico. La expresión de genes parentales, que no son inactivados por "imprinting", está asociada con 70% de los casos de tumores de Wilms y 20% de los casos esporádicos de cáncer de colon. Esto permite impulsar el estudio de la estructura de la cromatina en cáncer, la aplicación de compuestos que la pueden modificar para mejorar los efectos de la quimioterapia y radioterapia, abriendo paso a la "Terapia Cromatínica".

Palabras clave: Cáncer, epigénesis, cromatina, metilación, acetilación, desacetilación.


  1. 1. Wolffe AP, Hayes JJ. Chromatin disruption and modification. Nucleic Acids Res 1999;27:711-720.

  2. 2. Davie JR, Chadee DN. Regulation and regulatory parameters of histone modifications. J Cell Biochem 1998;30:203-213.

  3. 3. Kuo M-H, Zhou J, Jambeck P, Churchill MEA, Allis CD. Histone acetyltransferase activity of yeast Gcn5p is required for the activation to target genes in vivo. Genes Dev 1998;12:627-639.

  4. 4. Wong J, Patterton D, Imhof A, Shi Y-B, Wolffe AP. Distinct requirements for chromatin assembly in transcriptional repression by thyroid hormone receptor and histone deacetylase. EMBO J 1998;17:520-534.

  5. 5. Zhang D-E, Nielson DA. Histone acetylation in chicken erythrocytes. Rates of acetylation and evidence that histones in both active and potentially active chromatin are rapidly modified. Biochem J 1988;250:233-240.

  6. 6. Davie JR, Spencer VA. Control of histone modifications. J Cell Biochem Suppl 1999;32/33:141-148.

  7. 7. Lefebvre D, Mouchon A, Lefebvre B, Formstecher P. Binding of retinoic acid receptor heterodimers to DNA-role for histones NH2 termini. J Biol Chem 1998;273:12288-12295.

  8. 8. Perry M, Chalkley R. Histone acetylation increases the solubility of chromatin and occurs sequentially over most of the chromatin. J Biol Chem 1982;257:7336-7347.

  9. 9. Tse C, Sera T, Wolffe A P, Hansen JC. Disruption of higher order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III. Mol Cell Biol 1998;18:4629-4638.

  10. Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jeneuwein T. Regulation of chromatin structure by site-specific histone H3 methyltransferase. Nature 2000;406; 579-580.

  11. Lachner M, O´Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 2001;410:116-120.

  12. Nielson SJ, Schneider R, Bauer U-M, Bannister A J, Morrison A, O’Carroll D, Firstein R, Cleary M, Jenuwein T, Herrera RE, Kouzarides T. Rb targets histone H3 methylation and HP1 to promoters. Nature 2001;412:561-565.

  13. Luo RX, Postigo AA, Dean DC. Rb interacts with histone deacetylase to repress transcription Cell 1998;92:463-473.

  14. Zhang Y, Reinberg D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev 2001;15:2343-2360.

  15. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002;16:6-21.

  16. Bird AP, Wolffe AP. Methylation-induced repression- bets, braces and chromatin. Cell 1999;24:451-454.

  17. Momparler RL, Bovenzi V. DNA methylation and cancer. J Cell Physiol 2000;183:145-154.

  18. Knudsen AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820-823.

  19. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999;21:163-167.

  20. Herman JG, Merlo A, Mao L, Lapidus RG, Issa J-PJ, Davidson NE, Sidransky D, Baylin SB. Inactivation of the CDKN2/p16MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 1995;55:4525-4530.

  21. Hiraguri S, Godfrey T, Nakamura H, Graff J, Collins C, Shayesteh L, Dogget N, Johnson K, Wheelock M, Herman J, Baylin S, Pinkel D, Gray J. Mechanisms of inactivation of E-cadherin in breast cancer cell lines. Cancer Res 1998;58:1972-1977.

  22. Lapidus RG, Nass SJ, Davidson NE. The loss of estrogen and progesterone receptor gene expression in human breast cancer. J Mammary Gland Biol Neoplasia 1998;3:85-94.

  23. Redner RL, Wang J, Johnson ML. Chromatin remodeling and leukemia: new therapeutic paradigms. Blood 1999;94:417-428.

  24. Crowe DL. Retinoic acid receptor b induces terminal differentiation of squamous cell carcinoma liens in the absence of cyclin-dependent kinases inhibitor expression. Cancer Res 1998;58:142-148.

  25. Rice JC, Futscher BW. Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promotor. Nucleic Acids Res 2000;28:3233-3239.

  26. Li Q, Ahuja N, Burger PC, Issa JP. Methylation and silencing of the thrombospondin-1 promoter in human cancer. Oncogene 1999;18:3284-3289.

  27. Armstrong JA, Emerson BM. Transcription of chromatin: these are complex times. Curr Opin Genet Dev 1998 8:165-172.

  28. Bazett-Jones DP, Cote J, Landel CC, Peterson CL, Workman JL. The SWI/SNF complex creates loop domains in DNA and polynucleosomal arrays can disrupt DNA-histone contacts within these domains. Mol Cell Biol 1999;19:1470-1478.

  29. Chakraborty S, Senyuk V, Nucifora G. Genetic lesions and perturbation of chromatin architecture: a road to cell transformation. J Cell Biochem 2001;82:310-325.

  30. Bochar DA, Wang L, Beniya H, Kinev A, Xue Y, Lane WS, Wang W, Kashanchi F, Shiekattar R. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 2000;102:257-265.

  31. Strobeck MW, Knudsen KE, Fribourg AF, DeCristofaro MF, Weissman BE, Imbalzano AN, Knudsen ES. BRG1 is required for RB-mediated cell cycle arrest. Proc Natl Acad Sci USA 2000;97:7748-7753.

  32. Pao GM, Janknecht R, Ruffner H, Hunter T, Verma IM. CBP/p300 interact and functions as transcriptional coactivators of BRCA1. Proc Natl Acad Sci USA 2000;97:1020-1025.

  33. Vassetzky YS, Hair A, Razin SV. Rearrangement of chromatin domains in cancer and development. J Cell Biochem Suppl 2000;35:54-60.

  34. Luderus MEE, de Graaf A, Mattia E, den Balen JL, Grande MA, de Jong L, Van Driel R. Binding of matrix attachment regions to lamin B1. Cell 1992;70:949-959.

  35. Berrios M, Osheroff N, Fisher A. In situ localization of DNA topoisomerase II, a major polypeptide component of the Drosophila nuclear matrix fraction. Proc Natl Acad Sci USA 1985;82:4142-4146.

  36. Linskens MH, Eijsermans A, Dijkwel PA. Comparative analysis of DNA loop length in non transformed and transformed hamster cells. Mutat Res 1987;178:245-256.

  37. Oberhammer F, Wilson JW, Dive C, Morris ID, Hickman JA, Wakeling AE, Walker PR, Sikorska M. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 1993;12:3679-3684.

  38. Razin SV, Kekelidze MG, Lukanidin EM, Scherrer K, Georgiev GP. Replication origins are attached to the nuclear skeleton. Nucl Acids Res 1986;14:8189-8207.

  39. Tilghman SM. The sins of the fathers and mothers: genomic imprinting in mammalian development. Cell 1999;96:185-193.

  40. Thompson SL, Konfortova G, Gregory RI, Reik W, Dean W, Feil R. Environmental effects on genomic imprinting in mammals. Toxicol Lett 2001;120:143-150.

  41. Feinberg AP. Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction. Cancer Res 1999;59:1743s-1746s.

  42. Frühwald MC, Plass CH. Global and gene-specific methylation patterns in cancer: aspects of tumor biology and clinical potential. Mol Genet Metab 2002;75:1-16.

  43. Nakagawa H. Chadwick RB, Peltomaki P, Plass C, Nakamura Y, de La Chapelle A. From the cover: loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc Natl Acad Sci USA 2001;98:591-596.

  44. Goodman RH, Smolik S. CBP/p300 in cell growth, transformation and development. Genes Dev 2000;14:1553-1577.

  45. Champagne N, Bertos NR, Pelletier N, Wang AH, Vezmar M, Yang Y, Heng HH, Yang X. Identification of human histone acetyltransferase related to monocytic leukemia zinc finger protein. J Biol Chem 1999;274:28528-28536.

  46. Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, Housman D, Dogget NA, Rowley JD. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11; 16)(q23; p13.3). Proc Natl Acad Sci USA 1997;94:8732-8737.

  47. Lavau C, Du C, Thirman M, Zeleznik-Le N. Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia. EMBO J 2000;19:4655-4664.

  48. Kennison JA. The polycomb and trithorax group proteins of Drosophila: trans-regulators of homeotic gene function. Annu Rev Genet 1995;29:289-303.

  49. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukemia. Nature 1999;391:815-818.

  50. Lenny N, Wetendorf JJ, Heibert SW. Transcriptional regulation during myelopoiesis. Mol Biol Rep 1997;24:157-168.

  51. Kitabayashi I, Yokoyama A, Shimizu K, Ohki M. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J 1998;17:2994-3004.

  52. Lutterbach B, Westendorf JJ, Linggi B, Paten A, Moniwa M, Davie JR, Huynh KD, Bardwell VJ, Lavinsky RM, Rosenfeld MG, Glass C, Seto E, Heibert SW. ETO, a target of t(8;21) in acute leukemia, interacts with the NCoR and mSin3 co-repressors. Mol Cell Biol 1998;18: 7176-7184.

  53. Gamou T, Kitamura E, Hosoda F, Shimizu K, Shinohara K, Hayashi Y, Nagase T, Yokoyama Y, Ohki M. The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. Blood 1998;91:4028-4037.

  54. Nucifora G, Rowley JD. AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 1995;86:1-14.

  55. Morrow CS, Cowan KH. Mechanisms of antineoplastic drug resistance. In: De Vita VT Jr, Hellamn S, Rosenberg SA editors. Cancer principles and practice of oncology 4th ed. JB Lippincott Co. 4th edition. Philadelphia, PA, USA: 1993. p. 340-348.

  56. Zwiebel JA. New agents for acute myelogenous leukemia. Leukemia 2000;14:488-490.

  57. Kim GD, Choi YH, Dimtchev A, Jeong SJ, Dritschilo A, Jung M. Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase. J Biol Chem 1999;274:31127-31130.

  58. Wang CH, Fu M, Mani S, Wadler S, Senderowicz AM, Pestell RG. Histone acetylation and the cell cycle in cancer. Front Biosci 2001;6:d610-d629.

  59. Archer SY, Hodin RA. Histone acetylation and cancer. Curr Opin Genet Dev 1999;9:171-174.

>Revistas >Gaceta Médica de México >Año2002, No. 6

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