Changes in expression of imprinted genes following treatment of human cancer cell lines with non-mutagenic or mutagenic carcinogens.
It remains possible that chemicals that act by mutagenic mechanisms as well as chemicals that do not induce gene mutations may affect epigenetic gene expression. To test the possibility, we investigated the ability of both types of chemicals to alter the expression of five imprinted genes, PEG3, SNRPN, NDN, ZAC and H19, using two human colon cancer cell lines and a human breast cancer cell line. The expression of imprinted genes was changed by some non-mutagenic and mutagenic carcinogens independent of their mutagenic activity. The genes most commonly exhibiting the changes in expression were SNRPN and PEG3. Alterations of the expression of NDN and ZAC were also observed in some conditions. Methylation-specific PCR and chromatin immunoprecipitation assays suggest the possibility that changes in the expression of SNRPN may be associated with DNA hypomethylation and histone acetylation of the promoters and euchromatinization of the heterochromatic domains of the promoters. Changes in expression of the imprinted genes, PEG3 and NDN, were also observed in cells immortalized by treatment of normal human fibroblasts with 4-nitroquinoline 1-oxide or aflatoxin B1. We previously demonstrated that expression of the cancer-related gene, INK4a, in these immortal cells was lost via epigenetic mechanisms. The results prove that, in cancer cells, some mutagenic or non-mutagenic carcinogens can epigenetically influence the transcription levels of imprinted genes and also suggest the possibility that some chemical carcinogens may have epigenetic carcinogenic effects in human cells.
Shibui
Takeo
T
Oral and Maxillofacial Surgery, The Nippon Dental University Hospital at Tokyo, Tokyo 102-8158, Japan.
Higo
Yukari
Y
Tsutsui
Takeo W
TW
Uchida
Minoru
M
Oshimura
Mitsuo
M
Barrett
J Carl
JC
Tsutsui
Takeki
T
D001324:Autoantigens / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects*; D018392:Genomic Imprinting / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017411:Ribonucleoproteins, Small Nuclear / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D055517:snRNP Core Proteins
D001324:Autoantigens; D002273:Carcinogens; D018797:Cell Cycle Proteins; D051741:Kruppel-Like Transcription Factors; C490820:PEG3 protein, human; C106464:PLAGL1 protein, human; D017411:Ribonucleoproteins, Small Nuclear; C526417:SNRPN protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D055517:snRNP Core Proteins