Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer

Steven A. Belinsky, Kristen J. Nikula, Stephen B Baylin, Jean Pierre J Issa

Research output: Contribution to journalArticle

Abstract

The association between increased DNA-methyltransferase (DNA-MTase) activity and tumor development suggests a fundamental role for this enzyme in the initiation and progression of cancer. A true functional role for DNA- MTase in the neoplastic process would be further substantiated if the target cells affected by the initiating carcinogen exhibit changes in enzyme activity. This hypothesis was addressed by examining DNA-MTase activity in alveolar type II (target) and Clara (nontarget) cells from A/J and C3H mice that exhibit high and low susceptibility, respectively, for lung tumor formation. Increased DNA-MTase activity was found only in the target alveolar type II cells of the susceptible A/J mouse and caused a marked increase in overall DNA methylation in these cells. Both DNA-MTase and DNA methylation changes were detected 7 days after carcinogen exposure and, thus, were early events in neoplastic evolution. Increased gene expression was also detected by RNA in situ hybridization in hypertrophic alveolar type II cells of carcinogen-treated A/J mice, indicating that elevated levels of expression may be a biomarker for premalignancy. Enzyme activity increased incrementally during lung cancer progression and coincided with increased expression of the DNA-MTase gene in hyperplasias, adenomas, and carcinomas. Thus, these results indicate that early increases in DNA-MTase activity are strongly associated with neoplastic development and constitute a key step in carcinogenesis. The detection of premalignant lung disease through increased DNA-MTase expression and the possibility of blocking the deleterious effects of this change with specific inhibitors will offer new intervention strategies for lung cancer.

Original languageEnglish (US)
Pages (from-to)4045-4050
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number9
DOIs
StatePublished - Apr 30 1996

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Cytosine
Methyltransferases
Lung Neoplasms
DNA
Carcinogens
Alveolar Epithelial Cells
DNA Methylation
Enzymes
Neoplastic Processes
Neoplasms
Inbred C3H Mouse
Adenoma
Lung Diseases
Hyperplasia
In Situ Hybridization
Carcinogenesis
Biomarkers
RNA
Carcinoma
Gene Expression

Keywords

  • A/J mouse
  • alveolar type II cell
  • biomarker
  • susceptibility

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer. / Belinsky, Steven A.; Nikula, Kristen J.; Baylin, Stephen B; Issa, Jean Pierre J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 9, 30.04.1996, p. 4045-4050.

Research output: Contribution to journalArticle

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