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ToxSci Advance Access published online on July 25, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg190
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received April 17, 2003; accepted June 28, 2003
© 2003 Society of Toxicology

Carcinogenicity

Progressive Alterations in Global and GC-Rich DNA Methylation During Tumorigenesis

R. E. Watson 1, G. M. Curtin 2, D. J. Doolittle 2, and J. I. Goodman 1*

1 Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824
2 R.J. Reynolds Tobacco Company, Research and Development, Winston-Salem, NC 27102

* To whom correspondence should be addressed. E-mail: goodman3{at}msu.edu.


  Abstract

DNA methylation plays a key role in the regulation of gene expression, and failure to maintain normal patterns of methylation often contributes to carcinogenesis. We have characterized progressive methylation changes during the promotion stage of carcinogenesis using a SENCAR mouse skin initiation/promotion tumorigenesis model. Mice were initiated with a dermal application of 75 µg dimethylbenz[a]anthracene (DMBA) and promoted with 9, 18, 27, and 36 mg cigarette smoke condensate (CSC) thrice weekly for time periods up to 29 wks, when a large increase in tumor number was produced by the highest three doses. Global and GC-specific methylation were assessed using SssI methylase and arbitrarily primed PCR, respectively. Changes in GC-specific methylation were dose- and time-dependent. CSC doses required to detect these changes were 27 mg at 6 wks and 18 mg at 9 wks. This effect appears to be reversible; changes in GC-specific methylation were lessmarked after 9 wks promotion with 27 mg CSC followed by 6 wks recovery in comparison to 9 and 15 wks promotion with 27 mg CSC and no recovery period. Both tumor and non-tumor tissue promoted with 27 mg CSC for 29 wks exhibited changes in GC-specific methylation that were more pronounced in tumors. Tumor tissue was globally hypomethylated whereas non-tumor tissue did not exhibit changes in global methylation. In conclusion, as expected for a mechanism underlying tumor promotion, CSC alters methylation in a threshold-exhibiting, reversible, progressive fashion during promotion. Progressive alterations in global and GC-rich methylation appear to be mechanistically important during tumor promotion.

Key Words: DNA methylation, tumorigenesis, promotion, SENCAR mouse, skin tumorigenesis, epigenetics .


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