The epigenetics of renal cell tumors: From biology to biomarkers

Frontiers in Genetics

Volumn 3, Issue MAY, 2012, Pages

  Henrique, Rui ^a,b   Luís, Ana Sílvia ^a   Jerónimo, Carmen ^a,b  

^a PORTUGUESE ONCOLOGY INSTITUTE   (Portugal)

^b UNIVERSITY OF PORTO   (Portugal)

Author keywords

Chromatin remodeling; DNA methylation; Epigenetic based therapeutics; Epigenetics; Histone post translational modifications; Kidney; MicroRNAs; Renal cell tumors

Indexed keywords

EID: 84875085619     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2012.00094     Document Type: Article

References (127)

1. Arai, E., Ushijima, S., Fujimoto, H., Hosoda, F., Shibata, T., Kondo, T., Yokoi, S., Imoto, I., Inazawa, J., Hirohashi, S., and Kanai, Y. (2009). Genome-wide DNA methylation profiles in both precan-cerous conditions and clear cell renal cell carcinomas are correlated with malignant potential and patient outcome. Carcinogenesis 30, 214-221.
2. Astuti, D., Da Silva, N. F., Dallol, A., Gentle, D., Martinsson, T., Kogner, P., Grundy, R., Kishida, T., Yao, M., Latif, F., and Maher, E. R. (2004). SLIT2 promoter methylation analysis in neuroblas-toma, Wilms tumour and renal cell carcinoma. Br. J. Cancer 90, 515-521.
3. Baldewijns, M. M., Van Vlodrop, I. J., Schouten, L. J., Soetekouw, P. M., De Bruine, A. P., and Van Engeland, M. (2008). Genetics and epigenetics of renal cell cancer. Biochim. Biophys. Acta 1785, 133-155.
4. Ballestar, E., and Esteller, M. (2005). Methyl-CpG-binding proteins in cancer: blaming the DNA methylation messenger. Biochem. Cell Biol. 83, 374-384.
5. Banks, R. E., Tirukonda, P., Taylor, C., Hornigold, N., Astuti, D., Cohen, D., Maher, E. R., Stanley, A. J., Harn-den, P., Joyce, A., Knowles, M., and Selby, P. J. (2006). Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res. 66, 2000-2011.
6. Battagli, C., Uzzo, R. G., Dulaimi, E., Ibanez De Caceres, I., Krassen-stein, R., Al-Saleem, T., Greenberg, R. E., and Cairns, P. (2003). Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients. Cancer Res. 63, 8695-8699.
7. Berdasco, M., and Esteller, M. (2011). DNA methylation in stem cell renewal and multipotency. Stem Cell Res. Ther. 2, 42.
8. Beyer, S., Kristensen, M. M., Jensen, K. S., Johansen, J. V., and Staller, P. (2008). The histone demethylases JMJD1A and JMJD2B are transcrip-tional targets of hypoxia-inducible factor HIE /. Biol. Chem. 283, 36542-36552.
9. Bloushtain-Qimron, N., Yao, J., Sny-der, E. L., Shipitsin, M., Campbell, L. L., Mani, S. A., Hu, M., Chen, H., Ustyansky, V., Antosiewicz, J. E., Argani, P., Halushka, M. K., Thomson, J. A., Pharoah, P., Porgador, A., Sukumar, S., Parsons, R., Richardson, A. L., Stampfer, M. R., Gelman, R. S., Nikolskaya, T., Nikolsky, Y., and Polyak, K. (2008). Cell type-specific DNA methylation patterns in the human breast. Proc. Natl. Acad. Sci. U.S.A. 105, 14076-14081.
10. Breault, J. E., Shiina, H., Igawa, M., Ribeiro-Filho, L. A., Deguchi, M., Enokida, H., Urakami, S., Terashima, M., Nakagawa, M., Kane, C. J., Carroll, P. R., and Dahiya, R. (2005). Methylation of the gamma-catenin gene is associated with poor prognosis of renal cell carcinoma. Clin. Cancer Res. 11, 557-564.
11. Cha, T. L., Chuang, M. J., Wu, S. T., Sun, G. H., Chang, S. Y., Yu, D. S., Huang, S. M., Huan, S. K., Cheng, T. C., Chen, T. T., Fan, P. L., and Hsiao, P. W. (2009). Dual degradation of aurora A and B kinases by the histone deacetylase inhibitor LBH589 induces G2-M arrest and apoptosis of renal cancer cells. Clin. Cancer Res. 15, 840-850.
12. Chan, J. A., Krichevsky, A. M., and Kosik, K. S. (2005). MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65, 6029-6033.
13. Chen, H., Yan, Y., Davidson, T. L., Shinkai, Y., and Costa, M. (2006). Hypoxic stress induces dimethy-lated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells. Cancer Res. 66, 9009-9016.
14. Cho, M., Uemura, H., Kim, S. C., Kawada, Y., Yoshida, K., Hirao, Y., Konishi, N., Saga, S., and Yoshikawa, K. (2001). Hypomethylation of the MN/CA9 promoter and upregulated MN/CA9 expression in human renal cell carcinoma. Br. J. Cancer 85, 563-567.
15. Chow, T. F., Mankaruos, M., Scorilas, A.,Youssef, Y., Girgis, A., Mossad, S., Metias, S., Rofael, Y., Honey, R. J., Stewart, R., Pace, K. T., and Yousef, G. M. (2010a). The miR-17-92 cluster is over expressed in and has an onco-genic effect on renal cell carcinoma. J. Urol. 183,743-751.
16. Chow, T. F., Youssef, Y M., Lianidou, E., Romaschin, A. D., Honey, R. J., Stewart, R., Pace, K. T., and Yousef, G. M. (2010b). Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis. Clin. Biochem. 43,150-158.
17. Christoph, F., Kempkensteffen, C., Weikert, S., Kollermann, J., Krause, H., Miller, K., Schostak, M., and Schrader, M. (2006a). Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer. Br. J. Cancer 95, 1701-1707.
18. Christoph, F., Weikert, S., Kempkensteffen, C., Krause, H., Schostak, M., Kollermann, J., Miller, K., and Schrader, M. (2006b). Promoter hypermethylation profile of kidney cancer with new proapop-totic p53 target genes and clinical implications. Clin. Cancer Res. 12, 5040-5046.
19. Clifford, S. C., Prowse, A. H., Affara, N. A., Buys, C. H., and Maher, E. R. (1998). Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer 22, 200-209.
20. Costa, V. L., Henrique, R., Danielsen, S. A., Eknaes, M., Patricio, P., Morais, A., Oliveira, J., Lothe, R. A., Teixeira, M. R., Lind, G. E., and Jeronimo, C. (2011). TCF21 and PCDH17 methylation: an innovative panel of bio-markers for a simultaneous detection of urological cancers. Epigenet-ics6, 1120-1130.
21. Costa, V. L., Henrique, R., Ribeiro, F. R., Pinto, M., Oliveira, J., Lobo, F., Teixeira, M. R., and Jeronimo, C. (2007). Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors. BMC Cancer 7, 133. doi:10.1186/1471-2407-7-133
22. Dahl, E., Wiesmann, F., Woenckhaus, M., Stoehr, R., Wild, P. J., Veeck, J., Knuchel, R., Klopocki, E., Sauter, G., Simon, R., Wieland, W. F., Walter, B., Denzinger, S., Hartmann, A., and Hammerschmied, C. G. (2007). Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma. Oncogene 26, 5680-5691.
23. Dalgliesh, G. L., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., Teague, J., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P. J., Forbes, S., Jia, M., Jones, D., Knott, H., Kok, C. Y., Lau, K. W., Leroy, C., Lin, M. L., Mcbride, D. J., Maddison, M., Maguire, S., Mclay, K., Menzies, A., Mironenko, T., Mulderrig, L., Mudie, L., O'Meara, S., Pleasance, E., Rajas-ingham, A., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P. S., Turrell, K., Dykema, K. J., Khoo, S. K., Petillo, D., Won-dergem, B., Anema, J., Kahnoski, R. J., Teh, B. T., Stratton, M. R., and Futreal, P. A. (2010). Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360-363.
24. Doi, A., Park, I. H., Wen, B., Murakami, P., Aryee, M. J., Irizarry, R., Herb, B., Ladd-Acosta, C., Rho, J., Loewer, S., Miller, J., Schlaeger, T., Daley, G. Q., and Feinberg, A. P. (2009). Differential methylation of tissue-and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat. Genet. 41, 1350-1353.
25. Dudziec, E., Miah, S., Choudhry, H. M., Owen, H. C., Blizard, S., Glover, M., Hamdy, E C., and Catto, J. W. (2011). Hypermethylation of CpG islands and shores around specific microRNAs and mirtrons is associated with the phenotype and presence of bladder cancer. Clin. Cancer Res. 17, 1287-1296.
26. Dulaimi, E., Ibanez De Caceres, I., Uzzo, R. G., Al-Saleem, T., Greenberg, R. E., Polascik, T. J., Babb, J. S., Grizzle, W E., and Cairns, P. (2004). Promoter hypermethylation profile of kidney cancer. Clin. Cancer Res. 10, 3972-3979.
27. Ehrlich, M. (2005). DNA methylation and cancer-associated genetic instability. Adv. Exp. Med. Biol. 570, 363-392.
28. Ellinger, J., Kahl, P., Mertens, C., Rogenhofer, S., Hauser, S., Hartmann, W., Bastian, P. J., But-tner, R., Muller, S. C., and Von Ruecker, A. (2010). Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma. Int. J. Cancer 127, 2360-2366.
29. Esteller, M. (2008). Epigenetics in cancer. N. Engl. J. Med. 358,1148-1159.
30. 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.
31. Feinberg, A. P., Ohlsson, R., and Henikoff, S. (2006). The epigenetic progenitor origin of human cancer. Nat. Rev. Genet. 7, 21-33.
32. Feinberg, A. P., and Tycko, B. (2004). The history of cancer epigenetics. Nat. Rev. Cancer 4, 143-153.
33. Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., and Parkin, D. M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893-2917.
34. Fraga, M. F., Ballestar, E., Villar-Garea, A., Boix-Chornet, M., Espada, J., Schotta, G., Bonaldi, T., Haydon, C., Ropero, S., Petrie, K., Iyer, N. G., Perez-Rosado, A., Calvo, E., Lopez, J. A., Cano, A., Calasanz, M. J., Colomer, D., Piris, M. A., Ahn, N., Imhof, A., Caldas, C., Jenuwein, T., and Esteller, M. (2005). Loss of acetylation at Lys16 and trimethy-lation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 37,391-400.
35. Fridman, E., Dotan, Z., Barshack, I., David, M. B., Dov, A., Tabak, S., Zion, O., Benjamin, S., Benjamin, H., Kuker, H., Avivi, C., Rosenblatt, K., Polak-Charcon, S., Ramon, J., Rosenfeld, N., and Spector, Y. (2010). Accurate molecular classification of renal tumors using microRNA expression. J. Mol. Diagn. 12, 687-696.
36. Frigola, J., Song, J., Stirzaker, C., Hin-shelwood, R. A., Peinado, M. A., and Clark, S. J. (2006). Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nat. Genet. 38, 540-549.
37. Fullgrabe, J., Kavanagh, E., and Joseph, B. (2011). Histone onco-modifications. Oncogene 30, 3391-3403.
38. Garzon, R., Calin, G. A., and Croce, C. M. (2009). MicroRNAs in cancer. Annu. Rev. Med. 60, 167-179.
39. Goldberg, A. D., Allis, C. D., and Bernstein, E. (2007). Epigenetics: a landscape takes shape. Cell 128,635-638.
40. Gonzalgo, M. L., Yegnasubramanian, S., Yan, G., Rogers, C. G., Nicol, T. L., Nelson, W. G., and Pavlovich, C. P. (2004). Molecular profiling and classification of sporadic renal cell carcinoma by quantitative methylation analysis. Clin. Cancer Res. 10, 7276-7283.
41. Guil, S., and Esteller, M. (2009). DNA methylomes, histone codes and miR-NAs: tying it all together. Int. J. Biochem. Cell Biol. 41, 87-95.
42. Gumz, M. L., Zou, H., Kreinest, P. A., Childs, A. C., Belmonte, L. S., Legrand, S. N., Wu, K. J., Luxon, B. A., Sinha, M., Parker, A. S., Sun, L. Z., Ahlquist, D. A., Wood, C. G., and Copland, J. A. (2007). Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. Clin. Cancer Res. 13, 4740-4749.
43. Guo, X., Shi, M., Sun, L., Wang, Y., Gui, Y., Cai, Z., and Duan, X. (2011). The expression of histone demethy-lase JMJD1A in renal cell carcinoma. Neoplasma 58, 153-157.
44. Halkidou, K., Gaughan, L., Cook, S., Leung, H. Y., Neal, D. E., and Rob-son, C. N. (2004). Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 59,177-189.
45. Henikoff, S. (2008). Nucleosome desta-bilization in the epigenetic regulation of gene expression. Nat. Rev. Genet. 9, 15-26.
46. Herman, J. G., Latif, F., Weng, Y., Lerman, M. I., Zbar, B., Liu, S., Samid, D., Duan, D. S., Gnarra, J. R., Linehan, W. M., and Baylin, S. B. (1994). Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl. Acad. Sci. U.S.A. 91, 9700-9704.
47. Herman, J. G., Merlo, A., Mao, L., Lapidus, R. G., Issa, J. P., Davidson, N. E., Sidransky, D., and Baylin, S. B. (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.
48. Hinz, S., Weikert, S., Magheli, A., Hoffmann, M., Engers, R., Miller, K., and Kempkensteffen, C. (2009). Expression profile of the polycomb group protein enhancer of Zeste homo-logue 2 and its prognostic relevance in renal cell carcinoma. J. Urol. 182, 2920-2925.
49. Hirata, H., Hinoda, Y., Nakajima, K., Kawamoto, K., Kikuno, N., Kawakami, K., Yamamura, S., Ueno, K., Majid, S., Saini, S., Ishii, N., and Dahiya, R. (2009). Wnt antagonist gene DKK2 is epigenetically silenced and inhibits renal cancer progression through apoptotic and cell cycle pathways. Clin. Cancer Res. 15,5678-5687.
50. Hoque, M. O., Begum, S., Topaloglu, O., Jeronimo, C., Mambo, E.,Westra, W. H., Califano, J. A., and Sidransky, D. (2004). Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine, and serum DNA of patients with renal cancer. Cancer Res. 64,5511-5517.
51. Ibanez De Caceres, I., Dulaimi, E., Hoffman, A. M., Al-Saleem, T., Uzzo, R. G., and Cairns, P. (2006). Identification of novel target genes by an epigenetic reactivation screen of renal cancer. Cancer Res. 66,5021-5028.
52. Irizarry, R. A., Ladd-Acosta, C., Wen, B., Wu, Z., Montano, C., Onyango, P., Cui, H., Gabo, K., Rongione, M., Webster, M., Ji, H., Potash, J. B., Sabunciyan, S., and Feinberg, A. P. (2009). The human colon cancer methylome shows similar hypo-and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 41, 178-186.
53. Johnson, A. B., Denko, N., and Barton, M. C. (2008). Hypoxia induces a novel signature of chromatin modifications and global repression of transcription. Mutat. Res. 640, 174-179.
54. Jones, J., Juengel, E., Mickuckyte, A., Hudak, L., Wedel, S., Jonas, D., and Blaheta, R. A. (2009a). The histone deacetylase inhibitor valproic acid alters growth properties of renal cell carcinoma in vitro and in vivo. J. Cell. Mol. Med. 13, 2376-2385.
55. Jones, J., Juengel, E., Mickuckyte, A., Hudak, L., Wedel, S., Jonas, D., Hintereder, G., and Blaheta, R. A. (2009b). Valproic acid blocks adhesion of renal cell carcinoma cells to endothelium and extracellular matrix. J. Cell. Mol. Med. 13, 2342-2352.
56. Juan, D., Alexe, G., Antes, T., Liu, H., Madabhushi, A., Delisi, C., Ganesan, S.,Bhanot, G.,and Liou,L. S. (2010). Identification of a microRNA panel for clear-cell kidney cancer. Urology 75,835-841.
57. Juengel, E., Engler, J., Mickuckyte, A., Jones, J., Hudak, L., Jonas, D., and Blaheta, R. A. (2010). Effects of combined valproic acid and the epidermal growth factor/vascular endothe-lial growth factor receptor tyrosine kinase inhibitor AEE788 on renal cell carcinoma cell lines in vitro. BJU Int. 105, 549-557.
58. Jung, M., Mollenkopf, H. J., Grimm, C., Wagner, I., Albrecht, M., Waller, T., Pilarsky, C., Johannsen, M., Stephan, C., Lehrach, H., Nietfeld, W., Rudel, T., Jung, K., and Kristiansen, G. (2009). MicroRNA profiling of clear cell renal cell cancer identifies a robust signature to define renal malignancy. J. Cell. Mol. Med. 13, 3918-3928.
59. Kagara, I., Enokida, H., Kawakami, K., Matsuda, R., Toki, K., Nishimura, H., Chiyomaru, T., Tatarano, S., Ite-sako, T., Kawamoto, K., Nishiyama, K., Seki, N., and Nakagawa, M. (2008). CpG hypermethylation of the UCHL1 gene promoter is associated with pathogenesis and poor prognosis in renal cell carcinoma. J. Urol. 180,343-351.
60. Kapoor-Vazirani, P., Kagey, J. D., Powell, D. R., and Vertino, P. M. (2008). Role of hMOF-dependent histone H4 lysine 16 acetylation in the maintenance of TMS1/ASC gene activity. Cancer Res. 68, 6810-6821.
61. Kim, H. L., Seligson, D., Liu, X., Janzen, N., Bui, M. H., Yu, H., Shi, T., Bellde-grun, A. S., Horvath, S., and Figlin, R. A. (2005). Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J. Urol. 173, 1496-1501.
62. Kondo, Y.,Shen,L., Cheng, A. S., Ahmed, S., Boumber, Y., Charo, C., Yamochi, T., Urano, T., Furukawa, K., Kwabi-Addo, B., Gold, D. L., Sekido, Y., Huang, T. H., and Issa, J. P. (2008). Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat. Genet. 40, 741-750.
63. Kouzarides, T. (2007a). Chromatin modifications and their function. Cell 128, 693-705.
64. Kouzarides, T. (2007b). SnapShot: histone-modifying enzymes. Cell 131,822.
65. Lam, J. S., Leppert, J. T., Figlin, R. A., and Belldegrun, A. S. (2005). Role of molecular markers in the diagnosis and therapy of renal cell carcinoma. Urology 66, 1-9.
66. Lee, Y., Jeon, K., Lee, J. T., Kim, S., and Kim, V. N. (2002). MicroRNA maturation: stepwise processing and subcellular localization. EMBOJ. 21, 4663-4670.
67. Li, X., Chen, J., Hu, X., Huang, Y., Li, Z., Zhou, L., Tian, Z., Ma, H., Wu, Z., Chen, M., Han, Z., Peng, Z., Zhao, X., Liang, C., Wang, Y., Sun, L., Zhao, J., Jiang, B., Yang, H., Gui, Y., Cai, Z., and Zhang, X. (2011). Comparative mRNA and microRNA expression profiling of three genitourinary cancers reveals common hallmarks and cancer-specific molecular events. PLoS ONE 6, e22570. doi:10.1371/journal.pone.0022570
68. Lin, J. C., Jeong, S., Liang, G., Takai, D., Fatemi, M., Tsai, Y C, Egger, G., Gal-Yam, E. N., and Jones, P. A. (2007). Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell 12,432-444.
69. Linehan, W M., Srinivasan, R., and Schmidt, L. S. (2010). The genetic basis of kidney cancer: a metabolic disease. Nat. Rev. Urol. 7, 277-285.
70. Liu, H., Brannon, A. R., Reddy, A. R., Alexe, G., Seiler, M. W., Arreola, A., Oza, J. H., Yao, M., Juan, D., Liou, L. S., Ganesan, S., Levine, A. J., Rathmell, W. K., and Bhanot, G. V. (2010a). Identifying mRNA targets of microRNA dysregulated in cancer: with application to clear cell renal cell carcinoma. BMC Syst. Biol. 4, 51. doi:10.1186/1752-0509-4-51
71. Liu, W., Zabirnyk, O., Wang, H., Shiao, Y H., Nickerson, M. L., Khalil, S., Anderson, L. M., Perantoni, A. O., and Phang, J. M. (2010b). miR-23b targets proline oxidase, a novel tumor suppressor protein in renal cancer. Oncogene 29, 4914-4924.
72. Lopez-Beltran, A., Carrasco, J. C., Cheng, L., Scarpelli, M., Kirkali, Z., and Montironi, R. (2009). 2009 Update on the classification of renal epithelial tumors in adults. Int. J. Urol. 16,432-443.
73. Lopez-Serra, L., and Esteller, M. (2008). Proteins that bind methylated DNA and human cancer: reading the wrong words. Br. J. Cancer 98, 1881-1885.
74. Lu, J., Getz, G., Miska, E. A., Alvarez-Saavedra, E., Lamb, J., Peck, D., Sweet-Cordero, A., Ebert, B. L., Mak, R. H., Ferrando, A. A., Downing, J. R., Jacks, T., Horvitz, H. R., and Golub, T. R. (2005). MicroRNA expression profiles classify human cancers. Nature 435, 834-838.
75. Mahalingam, D., Medina, E. C., Esquivel, J. A. II, Espitia, C. M., Smith, S., Oberheu, K., Swords, R., Kelly, K. R., Mita, M. M., Mita, A. C., Carew, J. S., Giles, F. J., and Nawrocki, S. T. (2010). Vorinostat enhances the activity of temsirolimus in renal cell carcinoma through suppression of survivin levels. Clin. Cancer Res. 16,141-153.
76. McRonald, F. E., Morris, M. R., Gentle, D., Winchester, L., Baban, D., Ragoussis, J., Clarke, N. W., Brown, M. D., Kishida, T., Yao, M., Latif, E, and Maher, E. R. (2009). CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma. Mol. Cancer 8, 31.
77. Metzger, E., Wissmann, M., Yin, N., Muller, J. M., Schneider, R., Peters, A. H., Gunther, T., Buettner, R., and Schule, R. (2005). LSD1 demethy-lates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436-439.
78. Mikkelsen, T. S., Ku, M., Jaffe, D. B., Issac, B., Lieberman, E., Giannoukos, G., Alvarez, P., Brockman, W., Kim, T. K., Koche, R. P., Lee, W., Menden-hall, E., O'Donovan, A., Presser, A., Russ, C., Xie, X., Meissner, A., Wernig, M., Jaenisch, R., Nusbaum, C., Lander, E. S., and Bernstein, B. E. (2007). Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553-560.
79. Minardi, D., Lucarini, G., Filosa, A., Milanese, G., Zizzi, A., Di Primio, R., Montironi, R., and Muzzoni-gro, G. (2009). Prognostic role of global DNA-methylation and histone acetylation in pT1a clear cell renal carcinoma in partial nephrec-tomy specimens. J. Cell. Mol. Med. 13,2115-2121.
80. Morris, M. R., Gentle, D.,Abdulrahman, M., Clarke, N., Brown, M., Kishida, T., Yao, M., Teh, B. T., Latif, F., and Maher, E. R. (2008). Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma. Br. J. Cancer 98,496-501.
81. Morris, M. R., Gentle, D.,Abdulrahman, M., Maina, E. N., Gupta, K., Banks, R. E., Wiesener, M. S., Kishida, T., Yao, M., Teh, B., Latif, F., and Maher, E. R. (2005). Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma. Cancer Res. 65, 4598-4606.
82. Morris, M. R., Hesson, L. B., Wagner, K. J., Morgan, N. V., Astuti, D., Lees, R. D., Cooper, W. N., Lee, J., Gentle, D., Macdonald, F., Kishida, T., Grundy, R., Yao, M., Latif, F., and Maher, E. R. (2003). Multigene methylation analysis of Wilms tumour and adult renal cell carcinoma. Oncogene 22, 6794-6801.
83. Morris, M. R., Ricketts, C., Gentle, D., Abdulrahman, M., Clarke, N., Brown, M., Kishida, T., Yao, M., Latif, E, and Maher, E. R. (2010). Identification of candidate tumour suppressor genes frequently methylated in renal cell carcinoma. Oncogene 29, 2104-2117.
84. Morris, M. R., Ricketts, C. J., Gentle, D., Mcronald, F., Carli, N., Khalili, H., Brown, M., Kishida, T., Yao, M., Banks, R. E., Clarke, N., Latif, F., and Maher, E. R. (2011). Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma. Oncogene 30, 1390-1401.
85. Mosashvilli, D., Kahl, P., Mertens, C., Holzapfel, S., Rogenhofer, S., Hauser, S., Buttner, R., Von Ruecker, A., Muller, S. C., and Ellinger, J. (2010). Global histone acetylation levels: prognostic relevance in patients with renal cell carcinoma. CancerSci. 101, 2664-2669.
86. Mulero-Navarro, S., and Esteller, M. (2008). Epigenetic biomarkers for human cancer: the time is now. Crit. Rev. Oncol. Hematol. 68, 1-11.
87. Nakada, C., Matsuura, K., Tsukamoto, Y., Tanigawa, M., Yoshimoto, T., Narimatsu, T., Nguyen, L. T., Hijiya, N., Uchida, T., Sato, F., Mimata, H., Seto, M., and Moriyama, M. (2008). Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c. J. Pathol. 216,418-427.
88. Neal, C. S., Michael, M. Z., Rawlings, L. H., Van Der Hoek, M. B., and Gleadle, J. M. (2010). The VHL-dependent regulation of microRNAs in renal cancer. BMC Med. 8, 64. doi:10.1186/1741-7015-8-64
89. Nguyen, C. T., Weisenberger, D. J., Velicescu, M., Gonzales, F. A., Lin, J. C., Liang, G., and Jones, P. A. (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.
90. Paiva, F., Duarte-Pereira, S., Costa, V. L., Ramalho-Carvalho, J., Patricio, P., Ribeiro, E R., Lobo, F., Oliveira, J., Jeronimo, C., and Henrique, R. (2011). Functional and epigenetic characterization of the KRT19 gene in renal cell neoplasms. DNA Cell Biol. 30, 85-90.
91. Peters, I., Rehmet, K., Wilke, N., Kuczyk, M. A., Hennenlotter, J., Eilers, T., Machtens, S., Jonas, U., and Serth, J. (2007). RASSF1A promoter methylation and expression analysis in normal and neoplastic kidney indicates a role in early tumorigenesis. Mol. Cancer 6, 49.
92. Petillo, D., Kort, E. J., Anema, J., Furge, K. A., Yang, X. J., and Teh, B. T. (2009). MicroRNA profiling of human kidney cancer subtypes. Int. J. Oncol. 35, 109-114.
93. Pollard, P. J., Loenarz, C., Mole, D. R., Mcdonough, M. A., Gleadle, J. M., Schofield, C. J., and Rat-cliffe, P. J. (2008). Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha. Biochem. J. 416, 387-394.
94. Rathmell, W. K., and Chen, S. (2008). VHL inactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment. Expert Rev. Anticancer Ther. 8, 63-73.
95. Rini, B. I., Campbell, S. C., and Escud-ier, B. (2009). Renal cell carcinoma. Lancet 373,1119-1132.
96. Rodriguez-Paredes, M., and Esteller, M. (2011). Cancer epigenetics reaches mainstream oncology. Nat. Med. 17, 330-339.
97. Scelo, G., and Brennan, P. (2007). The epidemiology of bladder and kidney cancer. Nat. Clin. Pract. Urol. 4, 205-217.
98. Schulte, J. H., Lim, S., Schramm, A., Friedrichs, N., Koster, J., Versteeg, R., Ora, I., Pajtler, K., Klein-Hitpass, L., Kuhfittig-Kulle, S., Metzger, E., Schule, R., Eggert, A., Buettner, R., and Kirfel, J. (2009). Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblas-toma: implications for therapy. Cancer Res. 69,2065-2071
99. Seitz, H., Youngson, N., Lin, S. P., Dal-bert, S., Paulsen, M., Bachellerie, J. P., Ferguson-Smith, A. C., and Cavaille, J. (2003). Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retro transposon-like gene. Nat. Genet. 34, 261-262.
100. Seliger, B., Handke, D., Schabel, E., Bukur, J., Lichtenfels, R., and Dammann, R. (2009). Epigenetic control of the ubiquitin carboxyl terminal hydrolase 1 in renal cell carcinoma. J. Transl. Med. 7, 90.
101. Seligson, D. B., Horvath, S., Mcbrian, M. A., Mah, V., Yu, H., Tze, S., Wang, Q., Chia, D., Goodglick, L., and Kurdis-tani, S. K. (2009). Global levels of histone modifications predict prognosis in different cancers. Am. J. Pathol. 174, 1619-1628.
102. Shang, D., Liu, Y., Xu, X., Han, T., and Tian, Y. (2011). 5-Aza-2-deoxycytidine enhances susceptibility of renal cell carcinoma to pacli-taxel by decreasing LEF1/phospho-beta-catenin expression. Cancer Lett. 311,230-236.
103. Sharma, S., Kelly, T. K., and Jones, P. A. (2010). Epigenetics in cancer. Carcinogenesis 31,27-36.
104. Shenouda, S. K., and Alahari, S. K. (2009). MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev. 28, 369-378.
105. Shi, Y. (2007). Histone lysine demethylases: emerging roles in development, physiology and disease. Nat. Rev. Genet. 8, 829-833.
106. Sinha, S., Dutta, S., Datta, K., Ghosh, A. K., and Mukhopadhyay, D. (2009). Von Hippel-Lindau gene product modulates TIS11B expression in renal cell carcinoma: impact on vascular endothelial growth factor expression in hypoxia. J. Biol. Chem. 284,32610-32618.
107. Slaby, O., Jancovicova, J., Lakomy, R., Svoboda, M., Poprach, A., Fabian, P., Kren, L., Michalek, J., and Vyzula, R. (2010). Expression of miRNA-106b in conventional renal cell carcinoma is a potential marker for prediction of early metastasis after nephrec-tomy. J. Exp. Clin. Cancer Res. 29, 90.
108. Song, J., Noh, J. H., Lee, J. H., Eun, J. W., Ahn, Y. M., Kim, S. Y., Lee, S. H., Park, W. S., Yoo, N. J., Lee, J. Y., and Nam, S. W. (2005). Increased expression of histone deacetylase 2 is found in human gastric cancer. Acta Pathol. Microbiol Immunol. Scand. 113,264-268.
109. Takano, Y., Iwata, H., Yano, Y., Miyazawa, M., Virgona, N., Sato, H., Ueno, K., and Yano, T. (2010). Up-regulation of connexin 32 gene by 5-aza-2-deoxycytidine enhances vinblastine-induced cytotoxicity in human renal carcinoma cells via the activation of JNK signalling. Biochem. Pharmacol. 80, 463-470.
110. To, K. K., Polgar, O., Huff, L. M., Morisaki, K., and Bates, S. E. (2008). Histone modifications at the ABCG2 promoter following treatment with histone deacetylase inhibitor mirror those in multidrug-resistant cells. Mol. Cancer Res. 6, 151-164.
111. Touma, S. E., Goldberg, J. S., Moench, P., Guo, X., Tickoo, S. K., Gudas, L. J., and Nanus, D. M. (2005). Retinoic acid and the histone deacetylase inhibitor trichostatin a inhibit the proliferation of human renal cell carcinoma in a xenograft tumor model. Clin. Cancer Res. 11,3558-3566.
112. Urakami, S., Shiina, H., Enokida, H., Hirata, H., Kawamoto, K., Kawakami, T.,Kikuno, N., Tanaka, Y., Majid, S., Nakagawa, M., Igawa, M., and Dahiya, R. (2006). Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA. Clin. Cancer Res. 12,6989-6997.
113. Vaissiere, T., Sawan, C., and Herceg, Z. (2008). Epigenetic interplay between histone modifications and DNA methylation in gene silencing. MU tat. Res. 659,40-48.
114. Valera, V A., Walter, B. A., Linehan, W. M., and Merino, M. J. (2011). Regulatory effects of microRNA-92 (miR-92) on VHL gene expression and the hypoxic activation of miR-210 in clear cell renal cell carcinoma. J. Cancer 2, 515-526.
115. Valk-Lingbeek, M. E., Bruggeman, S. W., and Van Lohuizen, M. (2004). Stem cells and cancer; the polycomb connection. Cell 118,409-418.
116. van Haaften, G., Dalgliesh, G. L., Davies, H., Chen, L., Bignell, G., Greenman, C., Edkins, S., Hardy, C., OMeara, S., Teague, J., Butler, A., Hinton, J., Latimer, C., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P. J., Cole, J., Forbes, S., Jia, M., Jones, D., Kok, C. Y., Leroy, C., Lin, M. L., Mcbride, D. J., Maddison, M., Maquire, S., Mclay, K., Men-zies, A., Mironenko, T., Mulderrig, L., Mudie, L., Pleasance, E., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P. S., Turner, R., Turrell,K.,Varian,J.,West,S.,Widaa, S., Wray, P., Collins, V P., Ichimura, K., Law, S., Wong, J., Yuen, S. T., Leung, S. Y., Tonon, G., Depinho, R. A., Tai, Y. T., Anderson, K. C., Kahnoski, R. J., Massie, A., Khoo, S. K., Teh, B. T., Stratton, M. R., and Futreal, P. A. (2009). Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521-523.
117. van Vlodrop, I. J., Baldewijns, M. M., Smits, K. M., Schouten, L. J., Van Neste, L., Van Criekinge, W., Van Poppel, H., Lerut, E., Schuebel, K. E., Ahuja, N., Herman, J. G., De Bru-ine, A. P., and Van Engeland, M. (2010). Prognostic significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear cell renal cell carcinoma. Am. J. Pathol. 176, 575-584.
118. Varela, I., Tarpey, P., Raine, K., Huang, D., Ong, C. K., Stephens, P., Davies, H., Jones, D., Lin, M. L., Teague, J., Bignell, G., Butler, A., Cho, J., Dalgliesh, G. L., Galappaththige, D., Greenman, C., Hardy, C., Jia, M., Latimer, C., Lau, K. W., Marshall, J., Mclaren, S., Menzies, A., Mudie, L., Stebbings, L., Largaespada, D. A., Wessels, L. F., Richard, S., Kahnoski, R. J., Anema, J., Tuveson, D. A., Perez-Mancera, P. A., Mustonen, V., Fischer, A., Adams, D. J., Rust, A., Chan-On, W., Subimerb, C., Dykema, K., Furge, K., Campbell, P. J., Teh, B. T., Stratton, M. R., and Futreal, P. A. (2011). Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539-542.
119. Ventura, A., and Jacks, T. (2009). MicroRNAs and cancer: short RNAs go a long way. Cell 136, 586-591.
120. Veronese, A., Lupini, L., Consiglio, J., Visone, R., Ferracin, M., Fornari, E, Zanesi, N., Alder, H., D'Elia, G., Gramantieri, L., Bolondi, L., Lanza, G., Querzoli, P., Angioni, A., Croce, C. M., and Negrini, M. (2010). Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Res. 70, 3140-3149.
121. Wang, X. F., Qian, D. Z., Ren, M., Kato, Y., Wei, Y., Zhang, L., Fansler, Z., Clark, D., Nakanishi, O., and Pili, R. (2005). Epigenetic modulation of retinoic acid receptor beta2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma. Clin. Cancer Res. 11,3535-3542.
122. White, N. M., Khella, H. W., Grigull, J., Adzovic, S., Youssef, Y M., Honey, R. J., Stewart, R., Pace, K. T., Bjarna-son, G. A., Jewett, M. A., Evans, A. J., Gabril,M.,and Yousef, G.M. (2011). miRNA profiling in metastatic renal cell carcinoma reveals a tumour-suppressor effect for miR-215. Br. J. Cancer 105, 1741-1749.
123. Wulfken, L. M., Moritz, R., Ohlmann, C., Holdenrieder, S., Jung, V., Becker, E, Herrmann, E., Walgenbach-Brunagel, G., Von Ruecker, A., Muller, S. C., and Ellinger, J. (2011). MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels. PLoS ONE 6, e25787. doi:10.1371/jour-nal.pone.0025787
124. Yamada, D., Kikuchi, S., Williams, Y. N., Sakurai-Yageta, M., Masuda, M., Maruyama, T., Tomita, K., Gutmann, D. H., Kakizoe, T., Kitamura, T., Kanai, Y., and Murakami, Y (2006). Promoter hypermethylation of the potential tumor suppressor DAL-1/4. 1B gene in renal clear cell carcinoma. Int. J. Cancer 118, 916-923.
125. Youssef, Y M., White, N. M., Grigull, J., Krizova, A., Samy, C., Mejia-Guerrero, S., Evans, A., and Yousef, G. M. (2011). Accurate molecular classification of kidney cancer subtypes using microRNA signature. Eur. Urol. 59,721-730.
126. Zhang, B., Pan, X., Cobb, G. P., and Anderson, T. A. (2007). MicroRNAs as oncogenes and tumor suppressors. Dev. Biol. 302,1-12.
127. Zhou, L., Chen, J., Li, Z., Li, X., Hu, X., Huang, Y., Zhao, X., Liang, C., Wang, Y., Sun, L., Shi, M., Xu, X., Shen, F., Chen, M., Han, Z., Peng, Z., Zhai, Q., Zhang, Z., Yang, R., Ye, J., Guan, Z., Yang, H., Gui, Y., Wang, J., Cai, Z., and Zhang, X. (2010). Integrated profiling of microRNAs and mRNAs: microRNAs located on Xq27.3 associate with clear cell renal cell carcinoma. PLoS ONE 5, e15224. doi:10.1371/journal.pone.00 15224