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National Institute of Environmental Health Sciences

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Publication Detail

Title: Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis.

Authors: Phillips, Jennifer M; Yamamoto, Yukio; Negishi, Masahiko; Maronpot, Robert R; Goodman, Jay I

Published In Toxicol Sci, (2007 Mar)

Abstract: Altered DNA methylation is an epigenetic mechanism that plays a key role in the carcinogenesis process, and the nongenotoxic rodent hepatocarcinogen phenobarbital (PB) alters the methylation status of DNA in mouse liver. The constitutive active/androstane nuclear receptor (CAR) mediates half of the PB-induced hepatic gene expression changes and it is essential for liver tumor promotion in PB-treated mice. Here, a technique involving methylation-sensitive restriction digestion, arbitrarily primed PCR, and capillary electrophoresis was utilized to detect PB-induced regions of altered DNA methylation (RAMs) in CAR wildtype (WT) mice that are sensitive to promotion by PB and resistant CAR knockout (KO) mice. The CAR WT mice developed preneoplastic lesions after 23 weeks of PB treatment (precancerous) and liver tumors after 32 weeks, while the CAR KO mice did not develop tumors (Y. Yamamoto, et al., 2004, Cancer Res. 64, 7197-7200). Our goal was to discern those RAMs which are playing important roles in tumor formation by comparing the RAMs that form in sensitive and resistant groups of mice. Using this novel approach, 42 unique RAMs were identified in the precancerous as compared to the CAR KO, 23-week PB-treated tissue. Of these 42 RAMs, 14 carried forward to the tumor tissue, and additionally, 104 total unique RAMs were observed in the tumor tissue. These results indicate that there are unique RAMs occurring in the sensitive CAR WT mice and that a portion of these are seen in both the precancerous and tumor tissue. We hypothesize that these unique RAMs may be facilitating the tumorigenesis process, and these data support the view that DNA methylation plays a causative role in PB-induced tumorigenesis.

PubMed ID: 17172636 Exiting the NIEHS site

MeSH Terms: Analysis of Variance; Animals; Carcinogens; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; DNA Methylation*; DNA, Neoplasm/metabolism*; Diethylnitrosamine; Electrophoresis, Capillary; GC Rich Sequence; Gene Expression Regulation, Neoplastic*; Liver Neoplasms, Experimental/chemically induced; Liver Neoplasms, Experimental/genetics; Liver Neoplasms, Experimental/metabolism*; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Phenobarbital; Polymerase Chain Reaction/methods; Precancerous Conditions/chemically induced; Precancerous Conditions/genetics; Precancerous Conditions/metabolism*; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism*; Time Factors; Transcription Factors/genetics; Transcription Factors/metabolism*

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