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?