Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway.
Epigenomic changes in DNA methylation patterns are evident in a variety of cancers, including colorectal cancer (CRC). In addition, a large proportion of CRC tumors and cell lines harbor genetic mutations in the APC/beta-catenin/TCF transcription activation pathway. While several target genes have been proposed, a causal downstream agent between APC mutation and cancer has not been fully established. Because previous work implicates DNA methyltransferase (DMNT1) as a critical point in tumorigenesis and recent studies suggest that familial CRC also exhibits epigenetic alterations, we sought to investigate whether this gene might be regulated by APC in CRC. Reconstitution of wild type APC in HT-29 CRC cell lines reduced the expression of both a reporter gene driven by the minimal DNMT1 promoter and DNMT1 mRNA that is independent of cell growth stasis. We also provide evidence for a causal role of DNMT1 in CRC by demonstrating that antisense-driven reduction of DNMT1 mRNA inhibits anchorage-independent growth, an indicator of tumorigenesis, of CRC cells. These data support future consideration of DNMT1 as a target in the treatment of CRC.
Campbell
Paul M
PM
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada H3G 1Y6.
Szyf
Moshe
M
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013491:Suppressor Factors, Immunologic / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D012333:RNA, Messenger; D013491:Suppressor Factors, Immunologic; D015534:Trans-Activators; D051176:beta Catenin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human