Aberrant DNA methylation occurs in colon neoplasms arising in the azoxymethane colon cancer model.
Mouse models of intestinal tumors have advanced our understanding of the role of gene mutations in colorectal malignancy. However, the utility of these systems for studying the role of epigenetic alterations in intestinal neoplasms remains to be defined. Consequently, we assessed the role of aberrant DNA methylation in the azoxymethane (AOM) rodent model of colon cancer. AOM induced tumors display global DNA hypomethylation, which is similar to human colorectal cancer. We next assessed the methylation status of a panel of candidate genes previously shown to be aberrantly methylated in human cancer or in mouse models of malignant neoplasms. This analysis revealed different patterns of DNA methylation that were gene specific. Zik1 and Gja9 demonstrated cancer-specific aberrant DNA methylation, whereas, Cdkn2a/p16, Igfbp3, Mgmt, Id4, and Cxcr4 were methylated in both the AOM tumors and normal colon mucosa. No aberrant methylation of Dapk1 or Mlt1 was detected in the neoplasms, but normal colon mucosa samples displayed methylation of these genes. Finally, p19(Arf), Tslc1, Hltf, and Mlh1 were unmethylated in both the AOM tumors and normal colon mucosa. Thus, aberrant DNA methylation does occur in AOM tumors, although the frequency of aberrantly methylated genes appears to be less common than in human colorectal cancer. Additional studies are necessary to further characterize the patterns of aberrantly methylated genes in AOM tumors.
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Scott C
SC
Borinstein
Melissa
M
Conerly
Slavomir
S
Dzieciatkowski
Swati
S
Biswas
M Kay
MK
Washington
Patty
P
Trobridge
Steve
S
Henikoff
William M
WM
Grady
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001397:Azoxymethane; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics*; D017630:Connexins / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D064550:Death-Associated Protein Kinases; D004195:Disease Models, Animal; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000097004:Gap Junction delta-2 Protein
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D001397:Azoxymethane; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D017630:Connexins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D064550:Death-Associated Protein Kinases; D007136:Immunoglobulins; D051796:Inhibitor of Differentiation Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D008565:Membrane Proteins; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins; D019718:Receptors, CXCR4; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000097004:Gap Junction delta-2 Protein; C514936:CXCR4 protein, mouse; C498598:Cadm1 protein, mouse; C417743:Cdkn2a protein, mouse; C086479:Idb4 protein, mouse; C501485:Mlh1 protein, mouse; C421618:Mlt 1 protein, mouse; C109781:Smarca3 protein, mouse; C102314:Zik1 protein, mouse; C528331:MGMT protein, mouse; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse