Epigenetic targeting of the Nanog pathway and signaling networks during chemical carcinogenesis.
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/β- 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.
Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA and QIAGEN, 1012 C Bldg, Woolim-Lions Valley, 371-28 Gasandong, Gumchungu, Seoul, Republic of Korea.
Stella
S
Tommasi
Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA and QIAGEN, 1012 C Bldg, Woolim-Lions Valley, 371-28 Gasandong, Gumchungu, Seoul, Republic of Korea.
Albert
A
Zheng
QIAGEN, 1012 C Bldg, Woolim-Lions Valley, 371-28 Gasandong, Gumchungu, Seoul, Republic of Korea.
Jae-In
JI
Yoon
Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA and QIAGEN, 1012 C Bldg, Woolim-Lions Valley, 371-28 Gasandong, Gumchungu, Seoul, Republic of Korea besarati@med.usc.edu.
Ahmad
A
Besaratinia
D000818:Animals; D001580:Benzopyrenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016678:Genome; D018398:Homeodomain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071317:Nanog Homeobox Protein; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
D001580:Benzopyrenes; D002273:Carcinogens; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse