| First Author | Tommasi S | Year | 2014 |
| Journal | Carcinogenesis | Volume | 35 |
| Issue | 8 | Pages | 1726-36 |
| PubMed ID | 24480805 | Mgi Jnum | J:212504 |
| Mgi Id | MGI:5581582 | Doi | 10.1093/carcin/bgu026 |
| Citation | Tommasi S, et al. (2014) Epigenetic targeting of the Nanog pathway and signaling networks during chemical carcinogenesis. Carcinogenesis 35(8):1726-36 |
| abstractText | Chemical carcinogenesis has long been synonymous with genotoxicity, which entails DNA damage, genetic mutations and chromosomal abnormalities. The present study investigates a paradigm-shifting model in which epigenetic changes are key contributors to chemical carcinogenesis. Using genome-wide microarray-based analysis followed by conventional validation assays, we have progressively chronicled changes in the epigenetic landscape, as reflected in the patterns of DNA methylation, in the target organ of tumorigenesis in mice treated in vivo with a prototype chemical carcinogen (benzo[a]pyrene). Here, we demonstrate characteristic CpG island gain/loss of methylation and demethylation of repetitive DNA elements in carcinogen-treated mice, dependent on tumor progression. Alterations of the DNA methylome are accompanied by silencing of major DNA methyltransferases. Members of the Nanog pathway that establishes and maintains pluripotency in embryonic stem cells and possibly triggers uncontrolled proliferation of neoplastic cells are preferential targets of aberrant DNA methylation and concomitant gene dysregulation during chemical carcinogenesis. Several components of the MEK/ERK, JAK/STAT3, PI3K/AKT, WNT/beta- catenin and Shh signaling cascades, which are known to modulate Nanog expression, also show concurrent changes in the patterns of DNA methylation and gene expression. Our data support an epigenetic model of chemical carcinogenesis and suggest that surveillance of the epigenetic landscape, particularly at the loci and in the pathways identified in this study, may have utility for early detection and monitoring of the progression of malignancy. |
