title: Methyltransferase expression and tumor suppressor gene methylation in sporadic and familial colorectal cancer.
abstract: Molecular mechanisms underlying coordinated hypermethylation of multiple CpG islands in cancer remain unclear and studies of methyltransferase enzymes have arrived at conflicting results. We focused on DNMT1 and DNMT3B, DNA methyltransferases responsible for (de novo) methylation, and EZH2, histone (H3K27) methyltransferase, and examined their roles in tumor suppressor gene (TSG) methylation patterns we have previously established in sporadic and familial cancers. Our investigation comprised 165 tumors, stratified by tissue of origin (117 colorectal and 48 endometrial carcinomas) and sporadic vs. familial disease (57 sporadic vs. 60 familial, mainly Lynch syndrome, colorectal carcinomas). By immunohistochemical evaluation, EZH2 protein expression was associated with a TSG methylator phenotype. DNMT1, DNMT3B, and EZH2 were expressed at significantly higher levels in tumor vs. normal tissues. DNMT1 and EZH2 expression were positively correlated and higher in microsatellite-unstable vs. microsatellite-stable tumors, whether sporadic or hereditary. Ki-67 expression mirrored the same pattern. Promoter methylation of the methyltransferase genes themselves was addressed as a possible cause behind their altered expression. While DNMT1 or EZH2 did not show differential methylation between normal and tumor tissues, DNMT3B analysis corroborated the regulatory role of a distal promoter region. Our study shows that methyltransferase expression in cancer depends on the tissue of origin, microsatellite-instability status, cellular proliferation, and--in the case of DNMT3B--promoter methylation of the respective gene. Translation of methyltransferase expression into DNA methylation appears complex as suggested by the fact that except for EZH2, no clear association between methyltransferase protein expression and TSG methylation was observed.
authors: Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors: Emmi I
authors: EI
authors: Joensuu
authors: Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors: Taina T
authors: TT
authors: Nieminen
authors: Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors: Johanna E
authors: JE
authors: Lotsari
authors: Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.|Cytogenetics and Mutagenesis Unit, IMBICE-CONICET-CICPBA, La Plata, Argentina.
authors: Walter
authors: W
authors: Pavicic
authors: Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.|Department of Medical Laboratory Sciences, College of Health Sciences and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
authors: Wael M
authors: WM
authors: Abdel-Rahman
authors: Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors: Päivi
authors: P
authors: Peltomäki
mesh_terms: D000368:Aged; D049109:Cell Proliferation; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D053842:Microsatellite Instability; D008875:Middle Aged; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000071221:Enhancer of Zeste Homolog 2 Protein; D019394:Ki-67 Antigen; D063151:Polycomb Repressive Complex 2; D000097584:DNA Methyltransferase 3B; C000619380:DNMT1 protein, human; C498409:EZH2 protein, human