Methylation and Cancer
MI616Spring 2007
Andrew J. Pierce
Microbiology, Immunology and Molecular GeneticsGraduate Center for Toxicology
Markey Cancer CenterUniversity of Kentucky
Some considerations of methylation in cancer:
• cytosine methylation inactivating genes
• cytosine demethylation activating genes
• histone methylation in chromatin (eg. H3 lys4)
• response to methylating chemotherapy drugs
temozolomide O6-methyl guanine
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http://www.hscbklyn.edu/SUNY/Biochem/ALCOHOL/alcohol_folate_bkgd.html
cytosine 5-methylcytosineDNMT
Single Carbon Transfers
5-methylcytosine
• Occurs on CpG sequences• CpG is under-represented in the genome• CpG is over-represented near promoter sequences• reset at fertilization and established early in embryogenesis
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Clark SJ, Melki J. DNA methylation and gene silencing in cancer: which is the guilty party?Oncogene. 2002 Aug 12;21(35):5380-7.
G : 5-MeC A : TG : C
Geometry of 5-methycytosine
Robertson KD.DNA methylation and chromatin - unraveling the tangled web.Oncogene. 2002 Aug 12;21(35):5361-79.
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Model for methyl-directed gene deactivation
Genes altered by cytosine methylation in cancer
• Rb (tumor supressor)
• Mlh1 (mismatch repair)
• VHL (oxidative stress response)
• p16INK4A (CDK inhibitor)
• CpG island hypermethylation
Inactivation
Activation
• parasitic sequences eg: retrotransposons
• activate homologous recombination?
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Esteller M.CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.Oncogene. 2002 Aug 12;21(35):5427-40.
Genes deactivated by methylation in human cancers
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Esteller M.CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.Oncogene. 2002 Aug 12;21(35):5427-40.
11 different tumor-supressor genes
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Chemotherapy and reactivation of methylated genes
cytidine analogs irreversibly bind DNMT’s leading to genome-wide demethylation
Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.Oncogene. 2002 Aug 12;21(35):5483-95.
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Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.Oncogene. 2002 Aug 12;21(35):5483-95.
Das PM, Singal R.DNA methylation and cancer.J Clin Oncol. 2004 Nov 15;22(22):4632-42.
Methylation based cancer screening
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Histone methylation
Rice JC, Allis CD.Histone methylation versus histone acetylation: new insights into epigenetic regulation.Curr Opin Cell Biol. 2001 Jun;13(3):263-73.\
Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y.Histone demethylation mediated by the nuclear amine oxidase homolog LSD1.Cell. 2004 Dec 29;119(7):941-53.
A “real” histone demethylase
Methotrexate mediated inactivation of RAS?