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ToxSci Advance Access originally published online on February 20, 2009
Toxicological Sciences 2009 108(2):273-289; doi:10.1093/toxsci/kfp031
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Multiple Genes Exhibit Phenobarbital-Induced Constitutive Active/Androstane Receptor–Mediated DNA Methylation Changes during Liver Tumorigenesis and in Liver Tumors

Jennifer M. Phillips* and Jay I. Goodman{dagger},1

* Department of Biochemistry and Molecular Biology {dagger} Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824

1 To whom correspondence should be addressed at Department of Pharmacology and Toxicology, Michigan State University, B-440 Life Sciences Bldg., East Lansing, MI 48824. Fax: (517) 353-8915. E-mail: goodman3{at}msu.edu.

Received September 26, 2008; accepted February 9, 2009


  Abstract

The constitutive active/androstane receptor (CAR) mediates responses to the nongenotoxic rodent liver tumor promoter phenobarbital (PB), including certain gene expression changes, hepatomegaly, and tumor formation. Aberrant DNA methylation represents epigenetic events that can play multiple roles in tumorigenesis. Previously, 146 unique PB-induced regions of altered DNA methylation (RAMs) were observed in liver tumor–susceptible CAR wild-type (WT) mice (in 23 weeks, precancerous tissue, and 32 weeks, tumor tissue), as compared to the resistant knockout (KO). We believe that at least some of these might be key for tumorigenesis. In the current study, cloning and annotation of a subset (82%) of the unique RAMs revealed 47 genes exhibiting altered methylation; 17 are already implicated in cancer or related processes and, thus, we have identified 30 "new" candidate genes that might be involved in carcinogenesis due to an epigenetic alteration. These may contribute to tumor development through their involvement in angiogenesis, apoptosis, epithelial-mesenchymal cell transition, growth/survival, and invasion/migration/metastasis. We have also, previously, discerned unique PB-elicited RAMs in liver tumor-prone B6C3F1 mice, as compared to the relatively resistant C57BL/6 strain, at 2 or 4 weeks, and identified 51 genes exhibiting altered methylation. Importantly, 11 of these genes were identified from identical, unique RAMs discerned in both the sensitive B6C3F1 and CAR WT mice, thus representing an initial, potential candidate "fingerprint" which might serve as a biomarker for PB-induced tumorigenesis. These two studies reveal "new" genes whose epigenetic statuses changed uniquely in liver tumor–susceptible mice (B6C3F1 and CAR WT), as compared to their resistant counterparts (C57BL/6 and CAR KO, respectively), within a continuum of PB-induced tumorigenesis.

Key Words: CAR; constitutive active/androstane receptor; DNA methylation; epigenetic; mouse liver tumors; phenobarbital.


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J. M. Phillips, L. D. Burgoon, and J. I. Goodman
The Constitutive Active/Androstane Receptor Facilitates Unique Phenobarbital-Induced Expression Changes of Genes Involved in Key Pathways in Precancerous Liver and Liver Tumors
Toxicol. Sci., August 1, 2009; 110(2): 319 - 333.
[Abstract] [Full Text] [PDF]


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