Skip to main content
SpringerLink
Log in

APC and DNA Demethylation in Cell Fate Specification and Intestinal Cancer

  • Chapter
  • First Online:
Epigenetic Alterations in Oncogenesis

Part of the book series: Advances in Experimental Medicine and Biology ((volume 754))

Abstract

Most cases of colon cancer are initiated by mutation or loss of the tumor suppressor gene adenomatous polyposis coli (APC). APC controls many cellular functions including intestinal cell proliferation, differentiation, migration, and polarity. This chapter focuses on the role of APC in regulating a recently identified DNA demethylase system, consisting of a cytidine deaminase and a DNA glycosylase. A global decrease in DNA methylation is known to occur soon after loss of APC; however, how this occurs and its contribution to tumorigenesis has been unclear. In the absence of wild-type APC, ectopic expression of the DNA demethylase system leads to the hypomethylation of specific loci, including intestinal cell fating genes, and stabilizes intestinal cells in an undifferentiated state. Further, misregulation of this system may influence the acquisition of subsequent genetic mutations that drive tumorigenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Markowitz SD (2007) Aspirin and colon cancer–targeting prevention? N Engl J Med 356(21):2195–2198

    Article  PubMed  CAS  Google Scholar 

  2. Bienz M, Clevers H (2000) Linking colorectal cancer to Wnt signaling. Cell 103(2): 311–320

    Article  PubMed  CAS  Google Scholar 

  3. Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol 6:479–507

    Article  PubMed  CAS  Google Scholar 

  4. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2):159–170

    Article  PubMed  CAS  Google Scholar 

  5. Sunami E et al (2011) LINE-1 hypomethylation during primary colon cancer progression. PLoS One 6(4):e18884

    Article  PubMed  CAS  Google Scholar 

  6. Feinberg AP et al (1988) Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 48(5):1159–1161

    PubMed  CAS  Google Scholar 

  7. Cravo M et al (1996) Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma. Gut 39(3):434–438

    Article  PubMed  CAS  Google Scholar 

  8. Goelz SE et al (1985) Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228(4696):187–190

    Article  PubMed  CAS  Google Scholar 

  9. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767

    Article  PubMed  CAS  Google Scholar 

  10. Baker SJ et al (1990) p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 50(23):7717–7722

    PubMed  CAS  Google Scholar 

  11. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480

    Article  PubMed  CAS  Google Scholar 

  12. Sparks AB et al (1998) Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 58(6):1130–1134

    PubMed  CAS  Google Scholar 

  13. Morin PJ et al (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275(5307):1787–1790

    Article  PubMed  CAS  Google Scholar 

  14. Romagnolo B et al (1999) Intestinal dysplasia and adenoma in transgenic mice after overexpression of an activated beta-catenin. Cancer Res 59(16):3875–3879

    PubMed  CAS  Google Scholar 

  15. Blaker H et al (2003) Somatic mutations in familial adenomatous polyps. Nuclear translocation of beta-catenin requires more than biallelic APC inactivation. Am J Clin Pathol 120(3):418–423

    Article  PubMed  Google Scholar 

  16. Anderson CB, Neufeld KL, White RL (2002) Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proc Natl Acad Sci USA 99(13):8683–8688

    Article  PubMed  CAS  Google Scholar 

  17. Phelps RA et al (2009) A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 137(4):623–634

    Article  PubMed  CAS  Google Scholar 

  18. Wu X et al (2008) Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell 133(2):340–353

    Article  PubMed  CAS  Google Scholar 

  19. Caldwell CM, Green RA, Kaplan KB (2007) APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice. J Cell Biol 178(7):1109–1120

    Article  PubMed  CAS  Google Scholar 

  20. Caldwell CM, Kaplan KB (2009) The role of APC in mitosis and in chromosome instability. Adv Exp Med Biol 656:51–64

    Article  PubMed  CAS  Google Scholar 

  21. Green RA, Wollman R, Kaplan KB (2005) APC and EB1 function together in mitosis to regulate spindle dynamics and chromosome alignment. Mol Biol Cell 16(10):4609–4622

    Article  PubMed  CAS  Google Scholar 

  22. Quyn AJ et al (2010) Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue. Cell Stem Cell 6(2):175–181

    Article  PubMed  CAS  Google Scholar 

  23. Jette C et al (2004) The tumor suppressor adenomatous polyposis coli and caudal related homeodomain protein regulate expression of retinol dehydrogenase L. J Biol Chem 279(33):34397–34405

    Article  PubMed  CAS  Google Scholar 

  24. Nadauld LD et al (2006) Adenomatous polyposis coli control of C-terminal binding protein-1 stability regulates expression of intestinal retinol dehydrogenases. J Biol Chem 281(49): 37828–37835

    Article  PubMed  CAS  Google Scholar 

  25. Nadauld LD et al (2004) Adenomatous polyposis coli control of retinoic acid biosynthesis is critical for zebrafish intestinal development and differentiation. J Biol Chem 279(49): 51581–51589

    Article  PubMed  CAS  Google Scholar 

  26. Nadauld LD et al (2005) The zebrafish retinol dehydrogenase, rdh1l, is essential for intestinal development and is regulated by the tumor suppressor adenomatous polyposis coli. J Biol Chem 280(34):30490–30495

    Article  PubMed  CAS  Google Scholar 

  27. Mark M, Ghyselinck NB, Chambon P (2009) Function of retinoic acid receptors during embryonic development. Nucl Recept Signal 7:e002

    PubMed  Google Scholar 

  28. Duester G (2008) Retinoic acid synthesis and signaling during early organogenesis. Cell 134(6):921–931

    Article  PubMed  CAS  Google Scholar 

  29. Deb-Rinker P et al (2005) Sequential DNA methylation of the Nanog and Oct-4 upstream regions in human NT2 cells during neuronal differentiation. J Biol Chem 280(8):6257–6260

    Article  PubMed  CAS  Google Scholar 

  30. Fisher CL, Fisher AG (2011) Chromatin states in pluripotent, differentiated, and reprogrammed cells. Curr Opin Genet Dev 21(2):140–146

    Article  PubMed  CAS  Google Scholar 

  31. Wild L, Flanagan JM (2010) Genome-wide hypomethylation in cancer may be a passive consequence of transformation. Biochim Biophys Acta 1806(1):50–57

    PubMed  CAS  Google Scholar 

  32. Ito S et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047):1300–1303

    Article  PubMed  CAS  Google Scholar 

  33. Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324(5929):929–930

    Article  PubMed  CAS  Google Scholar 

  34. Tahiliani M et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929):930–935

    Article  PubMed  CAS  Google Scholar 

  35. Lister R et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315–322

    Article  PubMed  CAS  Google Scholar 

  36. Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25(10):1010–1022

    Article  PubMed  CAS  Google Scholar 

  37. Doi A et al (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(12):1350–1353

    Article  PubMed  CAS  Google Scholar 

  38. Irizarry RA et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41(2):178–186

    Article  PubMed  CAS  Google Scholar 

  39. Wu H et al (2010) Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329(5990):444–448

    Article  PubMed  CAS  Google Scholar 

  40. Shukla S et al (2011) CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479(7371):74–79

    Article  PubMed  CAS  Google Scholar 

  41. Hansen KD et al (2011) Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43(8):768–775

    Article  PubMed  CAS  Google Scholar 

  42. Suzuki K et al (2006) Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell 9(3):199–207

    Article  PubMed  CAS  Google Scholar 

  43. Rai K et al (2010) DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC. Cell 142(6):930–942

    Article  PubMed  CAS  Google Scholar 

  44. Barreto G et al (2007) Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445(7128):671–675

    Article  PubMed  CAS  Google Scholar 

  45. Rai K et al (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135(7):1201–1212

    Article  PubMed  CAS  Google Scholar 

  46. Morgan HD et al (2004) Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 279(50):52353–52360

    Article  PubMed  CAS  Google Scholar 

  47. Hendrich B et al (1999) Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mamm Genome 10(9):906–912

    Article  PubMed  CAS  Google Scholar 

  48. Wu P et al (2003) Mismatch repair in methylated DNA. Structure and activity of the mismatch-specific thymine glycosylase domain of methyl-CpG-binding protein MBD4. J Biol Chem 278(7):5285–5291

    Article  PubMed  CAS  Google Scholar 

  49. Blanc V et al (2007) Deletion of the AU-rich RNA binding protein Apobec-1 reduces intestinal tumor burden in Apc(min) mice. Cancer Res 67(18):8565–8573

    Article  PubMed  CAS  Google Scholar 

  50. Rosenberg BR et al (2011) Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3′ UTRs. Nat Struct Mol Biol 18(2):230–236

    Article  PubMed  CAS  Google Scholar 

  51. Anant S et al (2004) Apobec-1 protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase-2 expression. Gastroenterology 127(4):1139–1149

    Article  PubMed  CAS  Google Scholar 

  52. Oshima M et al (1996) Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87(5):803–809

    Article  PubMed  CAS  Google Scholar 

  53. Mayer W et al (2000) Demethylation of the zygotic paternal genome. Nature 403(6769): 501–502

    Article  PubMed  CAS  Google Scholar 

  54. Oswald J et al (2000) Active demethylation of the paternal genome in the mouse zygote. Curr Biol 10(8):475–478

    Article  PubMed  CAS  Google Scholar 

  55. Santos F et al (2002) Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol 241(1):172–182

    Article  PubMed  CAS  Google Scholar 

  56. Hajkova P et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117(1–2):15–23

    Article  PubMed  CAS  Google Scholar 

  57. Feng S, Jacobsen SE, Reik W (2010) Epigenetic reprogramming in plant and animal development. Science 330(6004):622–627

    Article  PubMed  CAS  Google Scholar 

  58. Popp C et al (2010) Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463(7284):1101–1105

    Article  PubMed  CAS  Google Scholar 

  59. Simonsson S, Gurdon J (2004) DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nat Cell Biol 6(10):984–990

    Article  PubMed  CAS  Google Scholar 

  60. Mikkelsen TS et al (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature 454(7200):49–55

    Article  PubMed  CAS  Google Scholar 

  61. Bhutani N et al (2010) Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463(7284):1042–1047

    Article  PubMed  CAS  Google Scholar 

  62. Eads CA, Nickel AE, Laird PW (2002) Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic Mice. Cancer Res 62(5):1296–1299

    PubMed  CAS  Google Scholar 

  63. Yamada Y et al (2005) Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci USA 102(38):13580–13585

    Article  PubMed  CAS  Google Scholar 

  64. Lin H et al (2006) Suppression of intestinal neoplasia by deletion of Dnmt3b. Mol Cell Biol 26(8):2976–2983

    Article  PubMed  CAS  Google Scholar 

  65. Laird PW et al (1995) Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81(2):197–205

    Article  PubMed  CAS  Google Scholar 

  66. Linhart HG et al (2007) Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev 21(23):3110–3122

    Article  PubMed  CAS  Google Scholar 

  67. Eads CA et al (2000) Fields of aberrant CpG island hypermethylation in Barrett’s esophagus and associated adenocarcinoma. Cancer Res 60(18):5021–5026

    PubMed  CAS  Google Scholar 

  68. Jones PA et al (1992) Methylation, mutation and cancer. Bioessays 14(1):33–36

    Article  PubMed  CAS  Google Scholar 

  69. Laird PW, Jaenisch R (1994) DNA methylation and cancer. Hum Mol Genet 3 Spec No:1487–1495

    PubMed  CAS  Google Scholar 

  70. Greenblatt MS et al (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54(18):4855–4878

    PubMed  CAS  Google Scholar 

  71. Holliday R, Grigg GW (1993) DNA methylation and mutation. Mutat Res 285(1):61–67

    Article  PubMed  CAS  Google Scholar 

  72. Wong E et al (2002) Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation. Proc Natl Acad Sci USA 99(23):14937–14942

    Article  PubMed  CAS  Google Scholar 

  73. Millar CB et al (2002) Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297(5580):403–405

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Oncological Sciences and Medicinal Chemistry, University of Utah, Salt Lake City, UT, 84112, USA

    Angela Andersen

  2. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA

    David A. Jones

Authors
  1. Angela Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David A. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Jones .

Editor information

Editors and Affiliations

  1. University of Nebraska Medical Center, Eppley Institute for Research in Cancer, 985950 Nebraska Medical Center, Omaha, 68198, Nebraska, USA

    Adam R. Karpf

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Andersen, A., Jones, D.A. (2013). APC and DNA Demethylation in Cell Fate Specification and Intestinal Cancer. In: Karpf, A. (eds) Epigenetic Alterations in Oncogenesis. Advances in Experimental Medicine and Biology, vol 754. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9967-2_8

Download citation

Publish with us

Policies and ethics

Search

Navigation