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Epigenetics of Colon Cancer

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Cancer Epigenetics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 863))

Abstract

Accumulation of genetic and epigenetic alterations transforms normal colonic epithelial cells to adenocarcinoma cells. Genetic alterations include mutations in tumor suppressor genes and oncogenes, whereas epigenetic mechanisms are defined as heritable alterations in gene expression that is independent of changes in the primary DNA sequence. Role of epigenetic mechanisms in development and maintenance of organ- and tissue-specific gene expression is now realized. Disturbances in epigenetic landscape can lead to malignant cellular makeover, and these heritable changes are maintained through various cycles of cell division that renders cells to have discrete identity with similar genetic information. Epigenetic alterations in colorectal cancer (CRC) that transform colonic epithelial cells into adenocarcinoma cells include aberrant DNA methylation, chromatin modifications, and noncoding RNAs, especially microRNA expression. CpG island DNA methylation and aberrant methylation of genes drive the initiation and progression of CRC. Histone modifications impinge on chromatin structure and gene expression and thus play an important role in gene silencing in CRC. DNA hypermethylation also leads to downregulation and inappropriate expression of certain microRNAs that act like tumor suppressor genes. Determining the causes and roles of epigenetic instability in CRC pathogenesis will lead to effective prevention and therapeutic strategies for patients with CRC. Epigenetic drugs that underscore the reversible nature of epigenetic events have led the possibility of epigenetic therapy as a treatment option in CRC.

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References

  1. Miyaki, M., Konishi, M., Kikuchi-Yanoshita, R., Enomoto, M., Igari, T., Tanaka, K., Muraoka, M., Takahashi, H., Amada, Y., Fukayama, M., and et al. (1994) Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 54 3011–3020.

    PubMed  CAS  Google Scholar 

  2. Esteller, M., Sparks, A., Toyota, M., Sanchez-Cespedes, M., Capella, G., Peinado, M. A., Gonzalez, S., Tarafa, G., Sidransky, D., Meltzer, S. J., Baylin, S. B., and Herman, J. G. (2000) Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 60 4366–4371.

    PubMed  CAS  Google Scholar 

  3. Veigl, M. L., Kasturi, L., Olechnowicz, J., Ma, A. H., Lutterbaugh, J. D., Periyasamy, S., Li, G. M., Drummond, J., Modrich, P. L., Sedwick, W. D., and Markowitz, S. D. (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A 95 8698–8702.

    Article  PubMed  CAS  Google Scholar 

  4. Alemayehu, A., Sebova, K., and Fridrichova, I. (2008) Redundant DNA methylation in colorectal cancers of Lynch-syndrome patients. Genes Chromosomes Cancer 47 906–914.

    Article  PubMed  CAS  Google Scholar 

  5. Grady, W. M. and Carethers, J. M. (2008) Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135, 1079–1099.

    Article  PubMed  CAS  Google Scholar 

  6. Ogino, S., Meyerhardt, J. A., Kawasaki, T., Clark, J. W., Ryan, D. P., Kulke, M. H., Enzinger, P. C., Wolpin, B. M., Loda, M., and Fuchs, C. S. (2007) CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma. Virchows Arch 450 529–537.

    Article  PubMed  CAS  Google Scholar 

  7. Jass, J. R. (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50 113–130.

    Article  PubMed  CAS  Google Scholar 

  8. Baylin, S. B. and Herman, J. G. (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16 168–174.

    Article  PubMed  CAS  Google Scholar 

  9. Li, H., Myeroff, L., Smiraglia, D., Romero, M. F., Pretlow, T. P., Kasturi, L., Lutterbaugh, J., Rerko, R. M., Casey, G., Issa, J. P., Willis, J., Willson, J. K., Plass, C., and Markowitz, S. D. (2003) SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A 100 8412–8417.

    Article  PubMed  CAS  Google Scholar 

  10. Chan, A. O., Broaddus, R. R., Houlihan, P. S., Issa, J. P., Hamilton, S. R., and Rashid, A. (2002) CpG island methylation in aberrant crypt foci of the colorectum. Am J Pathol 160 1823–1830.

    Article  PubMed  CAS  Google Scholar 

  11. Moinova, H. R., Chen, W. D., Shen, L., Smiraglia, D., Olechnowicz, J., Ravi, L., Kasturi, L., Myeroff, L., Plass, C., Parsons, R., Minna, J., Willson, J. K., Green, S. B., Issa, J. P., and Markowitz, S. D. (2002) HLTF gene silencing in human colon cancer. Proc Natl Acad Sci U S A 99 4562–4567.

    Article  PubMed  CAS  Google Scholar 

  12. Timp, W., Levchenko, A., and Feinberg, A. P. (2009) A new link between epigenetic progenitor lesions in cancer and the dynamics of signal transduction. Cell Cycle 8 383–390.

    Article  PubMed  CAS  Google Scholar 

  13. Weisenberger, D. J., Siegmund, K. D., Campan, M., Young, J., Long, T. I., Faasse, M. A., Kang, G. H., Widschwendter, M., Weener, D., Buchanan, D., Koh, H., Simms, L., Barker, M., Leggett, B., Levine, J., Kim, M., French, A. J., Thibodeau, S. N., Jass, J., Haile, R., and Laird, P. W. (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38 787–793.

    Article  PubMed  CAS  Google Scholar 

  14. Kondo, Y. and Issa, J. P. (2004) Epigenetic changes in colorectal cancer. Cancer Metastasis Rev 23 29–39.

    Article  PubMed  CAS  Google Scholar 

  15. Deng, G., Chen, A., Pong, E., and Kim, Y. S. (2001) Methylation in hMLH1 promoter interferes with its binding to transcription factor CBF and inhibits gene expression. Oncogene 20 7120–7127.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Zamore, P. D. and Haley, B. (2005) Ribo-gnome: the big world of small RNAs. Science 309 1519–1524.

    Article  PubMed  CAS  Google Scholar 

  19. Weber, B., Stresemann, C., Brueckner, B., and Lyko, F. (2007) Methylation of human microRNA genes in normal and neoplastic cells. Cell Cycle 6 1001–1005.

    Article  PubMed  CAS  Google Scholar 

  20. Xi, Y., Shalgi, R., Fodstad, O., Pilpel, Y., and Ju, J. (2006) Differentially regulated micro-RNAs and actively translated messenger RNA transcripts by tumor suppressor p53 in colon cancer. Clin Cancer Res 12 2014–2024.

    Article  PubMed  CAS  Google Scholar 

  21. Lujambio, A. and Esteller, M. (2007) CpG island hypermethylation of tumor suppressor microRNAs in human cancer. Cell Cycle 6 1455–1459.

    Article  PubMed  CAS  Google Scholar 

  22. Yang, L., Belaguli, N., and Berger, D. H. (2009) MicroRNA and colorectal cancer. World J Surg 33 638–646.

    Article  PubMed  Google Scholar 

  23. Akao, Y., Nakagawa, Y., and Naoe, T. (2006) let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull 29 903–906.

    Article  PubMed  CAS  Google Scholar 

  24. Han, L., Witmer, P. D., Casey, E., Valle, D., and Sukumar, S. (2007) DNA methylation regulates MicroRNA expression. Cancer Biol Ther 6 1284–1288.

    Article  PubMed  CAS  Google Scholar 

  25. Faber, C., Kirchner, T., and Hlubek, F. (2009) The impact of microRNAs on colorectal cancer. Virchows Arch 454 359–367.

    Article  PubMed  CAS  Google Scholar 

  26. Lujambio, A., Calin, G. A., Villanueva, A., Ropero, S., Sanchez-Cespedes, M., Blanco, D., Montuenga, L. M., Rossi, S., Nicoloso, M. S., Faller, W. J., Gallagher, W. M., Eccles, S. A., Croce, C. M., and Esteller, M. (2008) A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci U S A 105 13556–13561.

    Article  PubMed  CAS  Google Scholar 

  27. Lyko, F. and Brown, R. (2005) DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst 97 1498–1506.

    Article  PubMed  CAS  Google Scholar 

  28. Issa, J. P. and Kantarjian, H. M. (2009) Targeting DNA methylation. Clin Cancer Res 15 3938–3946.

    Article  PubMed  CAS  Google Scholar 

  29. Schaefer, M., Hagemann, S., Hanna, K., and Lyko, F. (2009) Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer Res 69 8127–8132.

    Article  PubMed  CAS  Google Scholar 

  30. Weber, B., Kimhi, S., Howard, G., Eden, A., and Lyko, F. (2010) Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription. Oncogene 29 5775–5784.

    Article  PubMed  CAS  Google Scholar 

  31. Silverman, L. R., Demakos, E. P., Peterson, B. L., Kornblith, A. B., Holland, J. C., Odchimar-Reissig, R., Stone, R. M., Nelson, D., Powell, B. L., DeCastro, C. M., Ellerton, J., Larson, R. A., Schiffer, C. A., and Holland, J. F. (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  PubMed  CAS  Google Scholar 

  32. Kantarjian, H., Issa, J. P., Rosenfeld, C. S., Bennett, J. M., Albitar, M., DiPersio, J., Klimek, V., Slack, J., de Castro, C., Ravandi, F., Helmer, R., 3rd, Shen, L., Nimer, S. D., Leavitt, R., Raza, A., and Saba, H. (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106 1794–1803.

    Article  PubMed  CAS  Google Scholar 

  33. Kim, Y. I. (2004) Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 13 511–519.

    PubMed  CAS  Google Scholar 

  34. Kim, Y. I. (2003) Role of folate in colon cancer development and progression. J Nutr 133 3731S-3739S.

    PubMed  CAS  Google Scholar 

  35. Giovannucci, E. (2002) Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr 132 2350S–2355S.

    PubMed  CAS  Google Scholar 

  36. Cole, B. F., Baron, J. A., Sandler, R. S., Haile, R. W., Ahnen, D. J., Bresalier, R. S., McKeown-Eyssen, G., Summers, R. W., Rothstein, R. I., Burke, C. A., Snover, D. C., Church, T. R., Allen, J. I., Robertson, D. J., Beck, G. J., Bond, J. H., Byers, T., Mandel, J. S., Mott, L. A., Pearson, L. H., Barry, E. L., Rees, J. R., Marcon, N., Saibil, F., Ueland, P. M., and Greenberg, E. R. (2007) Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297 2351–2359.

    Article  PubMed  CAS  Google Scholar 

  37. Kim, Y. I. (2004) Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr 80 1123–1128.

    PubMed  CAS  Google Scholar 

  38. Kumar, D. and Verma, M. (2009) Methods in cancer epigenetics and epidemiology. Methods Mol Biol 471 273–288.

    Article  PubMed  CAS  Google Scholar 

  39. Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., Verhaak, R. G., Hoadley, K. A., Hayes, D. N., Perou, C. M., Schmidt, H. K., Ding, L., Wilson, R. K., Van Den Berg, D., Shen, H., Bengtsson, H., Neuvial, P., Cope, L. M., Buckley, J., Herman, J. G., Baylin, S. B., Laird, P. W., and Aldape, K. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17 510–522.

    Google Scholar 

  40. Stephen, J. K., Chen, K. M., Shah, V., Havard, S., Kapke, A., Lu, M., Benninger, M. S., and Worsham, M. J. (2010) DNA hypermethylation markers of poor outcome in laryngeal cancer. Clin Epigenetics 1 61–69.

    Article  PubMed  CAS  Google Scholar 

  41. Hoefig, K. P., Thorns, C., Roehle, A., Kaehler, C., Wesche, K. O., Repsilber, D., Branke, B., Thiere, M., Feller, A. C., and Merz, H. (2008) Unlocking pathology archives for microRNA-profiling. Anticancer Res 28 119–123.

    PubMed  CAS  Google Scholar 

  42. Chen, C., Ridzon, D. A., Broomer, A. J., Zhou, Z., Lee, D. H., Nguyen, J. T., Barbisin, M., Xu, N. L., Mahuvakar, V. R., Andersen, M. R., Lao, K. Q., Livak, K. J., and Guegler, K. J. (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33 e179.

    Article  PubMed  Google Scholar 

  43. Zhang, Z. and Pugh, B. F. (2011) High-resolution genome-wide mapping of the primary structure of chromatin. Cell 144 175–186.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Hines Veterans Affairs Medical Center, Hines, IL, USA

    Sharad Khare

  2. Department of Medicine, Loyola University Chicago, Maywood, IL, USA

    Sharad Khare

  3. Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, MD, USA

    Mukesh Verma

Authors
  1. Sharad Khare
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  2. Mukesh Verma
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Corresponding author

Correspondence to Sharad Khare .

Editor information

Editors and Affiliations

  1. School of Medicine, Saba University, Saba, Dutch Antilles

    Ramona G. Dumitrescu

  2. National Institutes of Health (NIH), Div. Cancer Control &, National Cancer Institute, Executive Blvd. 6130Suite 5100, Bethesda, 20892-7324, Maryland, USA

    Mukesh Verma

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Khare, S., Verma, M. (2012). Epigenetics of Colon Cancer. In: Dumitrescu, R., Verma, M. (eds) Cancer Epigenetics. Methods in Molecular Biology, vol 863. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-612-8_10

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  • DOI: https://doi.org/10.1007/978-1-61779-612-8_10

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-611-1

  • Online ISBN: 978-1-61779-612-8

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