Cambios epigenéticos y cáncer: nueva visión de la transformación tumoral
Resumen
Los patrones epigenéticos aberrantes a nivel de la cromatina conllevan a una regulación transcripcional disfuncional, y hay evidencia creciente que esto representa uno de los agentes causales del desarrollo de procesos cancerígenos. Entre los cambios epigenéticos más importantes en cáncer destacan el estatus de metilación en el ADN y de acetilación en histonas. La metilación del ADN ocurre en residuos de citosina en el dinucleótido CpG, ubicadas en mayor medida en regiones promotoras de genes. Patrones aberrantes de hipermetilación en estas zonas causan la represión transcripcional de los genes afectados. Por otra parte, la acetilación de histonas está relacionada a una elevada actividad transcripcional. Enzimas desacetilasas de histonas (HDACs), sobre-expresadas en células cancerígenas, escinden estos grupos acetilo de las histonas, ocasionando un mayor empaquetamiento de la cromatina. Un gran número de genes implicados en la regulación del ciclo celular, reparación del ADN y muerte celular son silenciados por estas modificaciones en cáncer, resaltando los que poseen actividad supresora tumoral, lo cual provoca su inactivación, contribuyendo con la aparición de procesos cancerígenos. Debido a esto, el uso de marcadores epigenéticos típicos de tumores específicos como blancos terapéuticos está siendo evaluado, así como los posibles usos de agentes farmacológicos que reviertan estos cambios en humanos, lo cual pudiera contribuir con la re-expresión transcripcional de los genes afectados, abriendo un nuevo campo en la terapia anti-tumoral.
Palabras clave:
cáncer, expresión genética, ADN, terapia anti-tumoralReferencias
(1) Kristensen LS, Nielsen HM, Hansen LL. Epigenetics and cancer treatment. Eur J of Pharmacol. 2009; 625(1-3): 131-142.
(2) Dolinoy DC, Weidman JR, Jirtle RL. Epigenetic gene regulation: Linking early developmental environment to adult disease. Reprod Toxicol. 2007; 23(3): 297-307.
(3) Shones De, Zhao K. Genome-wide approaches to studying chromatin modifications. Nat Rev Genet. 2008; 9(3): 179-191.
(4) Bird A. Perceptions of epigenetics. Nature. 2007; 447(7143): 396-398.
(5) Jones PA, Baylin SB. The Epigenomics of Cancer. Cell. 2007; 128(4): 683-692.
(6) Martinet N, Bertrand P. Interpreting clinical assays for histone deacetylase inhibitors. Cancer Manag Res. 2011; 3: 117-141.
(7) Rajnakova A, Moochhala S, Goh PM, Ngoi S. Expression of nitric oxide synthase, cyclooxygenase, and p53 in different stages of human gastric cancer. Cancer Lett; 172(2): 177-185.
(8) Khulan B, Thompson RF, Ye K, Fazzari MJ, Suzuki M, Stasiek E, et al. Comparative isoschizomer profiling of cytosine methylation: The HELP assay. Genome Res. 2006; 16(8): 1046-1055.
(9) Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007; 8(4): 286- 298.
(10) Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6): 415-428.
(11) Feinberg AP, Ticko B. The history of cancer epigenetics. Nat Rev Cancer. 2004; 4(2): 143-153.
(12) Bird AP. CpG rich islands and the function of DNA methylation. Nature. 1986; 321(6067): 209-213.
(13) Zangi R, Arrieta A, Cossío FP. Mechanism of DNA Methylation: The Double Role of DNA as a Substrate and as a Cofactor. J Mol Biol. 2010; 400(3): 632-644.
(14) Esteller M. Aberrant DNA methylathion as a cancerinducing mechanism. Annu. Rev. Pharmacol. Toxicol. 2005; 45: 629-656.
(15) Esteller M. Epigenetics in Cancer. N Engl J Med. 2008; 358(11): 1148-1159.
(16) Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature. 1998; 395(6697): 89-93.
(17) Kondo Y, Shen L, Issa JP. Critical Role of Histone Methylation in Tumor Suppressor Gene Silencing in Colorectal Cancer. Mol Cell Biol. 2003; 23(1): 206-215.
(18) Teng IW, Hou PC, Lee KD, Chu PY, Yeh KT, Tseng MJ, et al. Targeted Methylation of Two Tumor Suppressor Genes ls Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells. Cancer Res. 2011; 71(13): 4653- 4663.
(19) Lopez-Serra L, Ballestar E, Fraga MF, Alaminos M, Setien F, Esteller M. A Profile of Methyl-CpG Binding Domain Protein Occupancy of Hypermethylated Promoter CpG Islands of Tumor Suppressor Genes in Human Cancer. Cancer Res. 2006; 66(17): 8342-8346.
(20) Ushijima T. Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer. 2005; 5(3): 223-231.
(21) Mathews C, Van Holde K. Biochemical. Ed. McGrawHill Interamericana 2da edición. Madrid, 2000.
(22) Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG. Aberrant patterns of DNA methylathion, chromatin formation and gene expression in cancer. Hum Mol Genet. 2001; 10(7): 687-692.
(23) Kondo Y, Shen L, Cheng AS, Ahmed S, Boumber Y, Charo C, et al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet. 2008; 40(6): 741-750.
(24) Dje N'Guessan P, Riediger F, Vardarova K, Scharf S, Eitel J, Opitz B, et al. Statin control oxidaded LDLmediated histone modifications and gene expression in cultured human endothelial cell. Arterioscler Thromb Vasc Biol. 2009; 29(3): 380-386.
(25) Wagner JM, Hackanson B, Lubbert M, Jung M. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenet. 2010; 1(3-4): 117-136.
(26) Fraga MF, Ballestar B, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 2005; 37(4): 391-400.
(27) Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl. Acad. Sci. 2000; 97(18): 10014-10019.
(28) Hauser C, Schuettengruber B, Bartl S, Lagger G, Seiser C. Activation of the Mouse Histone Deacetylase 1 Gene by Cooperative Histone Phosphorylation and Acetylation. Mol Cell Biol. 2002; 22(22): 7820-7830.
(29) Meng CF, Zhu XJ, Peng G, Dai DQ. Re-expression of methylation induced tumor suppressor gene silencing is associated with the state of histone modification in gastric cancer cell lines. World J Gastroenterol. 2007; 13(46): 6166- 6171.
(30) LairdP. The Powerand the promise ofDNA methylation markers. Nat Rev Cancer. 2003; 3(4): 253-266.
(31) Facchinetti F, Furegato S, Terrazzino S, Leon A. H202 Induces Upregulation of Fas and Fas Ligand Expression in NGF-Differentiated PC12 Cells: Modulation By CAMP. J Neurosci Res. 2002; 69:178-188.
(32) Bogenmann E, Peterson S, Maekawa K, Matsushima H. Regulation of NGF responsiveness in human neuroblastoma. Oncogene. 1998, 17(18): 2367-2376.
(33) Das A, Banik NL, Ray SK. Flavonoids Activated Caspases for Apoptosis in Human Glioblastoma T98G and U87MG Cells But Not in Human Normal Astrocytes. Cancer. 2010, 116(1): 164-176.
(34) Shim YH, Kang GH, Ro JY. Correlation of p16 hypermethylation with p16 protein loss in sporadic gastric carcinomas. Lab Invest. 2000; 80(5): 689-695.
(35) Lyko F, Brown R. DNA Methyltransferase Inhibitors and the Development of Epigenetic Cancer Therapies. J Natl Cancer Inst. 2005; 97(20): 1498-1506.
(36) Fang JY, Chen YX, Lu J, Lu R, Yang L, Zhu HY, et al. Epigenetic modification regulates both expression of tumor-associated genes and cell cycle progressing in human colon cancer cell lines: Colo-320 and SW1116. Cell Res. 2004; 14(3): 217-226.
(37) Brueckner B, Garcia R, Siedlecki P, Musch T, Kliem H, Zielenkiewicz P, et al. Epigenetic Reactivation of Tumor Suppressor Genes by a Novel Small-Molecule Inhibitor of Human DNA Methyltransferases. Cancer Res. 2005; 65(14): 6305-6311.
(38) LinX, Asgari K, Putzi MJ, Gage WR, Yu X, Cornblatt BS, et al. Reversal of GSTP1 CpG Island Hypermethylation and Reactivation of t-Class Glutathione S-Transferase (GSTP1) Expression in Human Prostate Cancer Cells by Treatment with Procainamide. Cancer Res. 2001; 61(24): 8611-8616.
(39) Villar Garea A, Fraga MF, Espada J, Esteler M. Procaine Is a DNA-demethylating Agent with Growthinhibitory Effects in Human Cancer Cells. Cancer Res. 2003; 63(16): 4984-4989.
(40) Datta J, Ghoshal K, Denny WA, Gamage SA, Brooke DG, Phiasivongsa P, et al. A New Class of QuinolineBased DNA Hypomethylating Agents Reactivates Tumor Suppressor Genes by Blocking DNA Methyltransferase 1 Activity and Inducing Its Degradation. Cancer Res. 2009; 69(10): 4277-85.
(41) Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the reexpression of genes silenced in cancer. Nat Genet. 1999; 21(1):103-107.
(42) Minuccis, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006; 6(1): 38-51.
(43) Pruitt K, Zinn RL, Ohm JE, Mcgarvey KM, Kang SH, Watkins DN, et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2006; 2(3). e40.
(44) Marks PA, Richon VM, Rifkind RA. Histone Deacetylase Inhibitors: Inducers of Differentiation or Apoptosis of Transformed Cells. J Natl Cancer Inst. 2000; 92(15):1210-1216.
(45) Chen YX, Fang JY, Zhu HY, Lu R, Cheng ZH, Qiu DK. Histone acetylation regulates p21WAF1 expression in human colon cancer cell lines. World J Gastroenterol. 2004; 10(18): 2643-2646.
(46) Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG, Davidsen SK. Gene Expression Profiling of Multiple Histone Deacetylase (HDAC) Inhibitors: Defining a Common Gene Set Produced by HDAC Inhibition in T24 and MDA Carcinoma Cell Lines. Mol Cancer Ther. 2003; 2(2): 151-163.
(47) Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol. 2005; 45: 495-528.
