Inhibition of DNA Methylation and Histone Deacetylation Prevents Murine Lung Cancer

Steven A. Belinsky, Donna M. Klinge, Christine A. Stidley, Jean Pierre Issa, James G. Herman, Thomas H. March, Stephen B Baylin

Research output: Contribution to journalArticle

Abstract

Disruption of one allele for the cytosine-DNA methyltransferase 1 (DNMT1) gene in mice with a germ-line mutation in a tumor suppressor gene was shown previously to reduce tumor formation in juvenile animals. This effect is now reproduced in our studies of mature mice where this genetic DNMT1 reduction leads to a 50% decrease in tobacco carcinogen-induced lung cancer and a similar reduction in DNMT activity in type II pneumocytes that give rise to the tumors. Short-term treatment of DNMT wild-type female mice with low doses of the demethylating agent 5-aza-2′-deoxycytidine decreased the incidence of neoplasms by 30%. Importantly, when 5-aza-2′-deoxycytidine was combined with the histone deacetylase inhibitor sodium phenylbutyrate, lung tumor development was significantly reduced by >50%; no effect was seen with phenylbutyrate alone. This identical combination of inhibitors also acts synergistically to cause re-expression of densely hypermethylated and transcriptionally silenced tumor suppressor genes in human cancer cells. Thus, reduction in DNMT and histone deacetylase activities that likely block epigenetically mediated gene silencing might provide a novel clinical strategy to help prevent the leading cause of cancer death in the United States.

Original languageEnglish (US)
Pages (from-to)7089-7093
Number of pages5
JournalCancer Research
Volume63
Issue number21
StatePublished - Nov 1 2003

Fingerprint

DNA Methylation
Histones
Lung Neoplasms
decitabine
Neoplasms
Methyltransferases
Tumor Suppressor Genes
Phenylbutyrates
Alveolar Epithelial Cells
Histone Deacetylase Inhibitors
Histone Deacetylases
Germ-Line Mutation
Cytosine
DNA
Gene Silencing
Carcinogens
Tobacco
Cause of Death
Alleles
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Belinsky, S. A., Klinge, D. M., Stidley, C. A., Issa, J. P., Herman, J. G., March, T. H., & Baylin, S. B. (2003). Inhibition of DNA Methylation and Histone Deacetylation Prevents Murine Lung Cancer. Cancer Research, 63(21), 7089-7093.

Inhibition of DNA Methylation and Histone Deacetylation Prevents Murine Lung Cancer. / Belinsky, Steven A.; Klinge, Donna M.; Stidley, Christine A.; Issa, Jean Pierre; Herman, James G.; March, Thomas H.; Baylin, Stephen B.

In: Cancer Research, Vol. 63, No. 21, 01.11.2003, p. 7089-7093.

Research output: Contribution to journalArticle

Belinsky, SA, Klinge, DM, Stidley, CA, Issa, JP, Herman, JG, March, TH & Baylin, SB 2003, 'Inhibition of DNA Methylation and Histone Deacetylation Prevents Murine Lung Cancer', Cancer Research, vol. 63, no. 21, pp. 7089-7093.
Belinsky SA, Klinge DM, Stidley CA, Issa JP, Herman JG, March TH et al. Inhibition of DNA Methylation and Histone Deacetylation Prevents Murine Lung Cancer. Cancer Research. 2003 Nov 1;63(21):7089-7093.
Belinsky, Steven A. ; Klinge, Donna M. ; Stidley, Christine A. ; Issa, Jean Pierre ; Herman, James G. ; March, Thomas H. ; Baylin, Stephen B. / Inhibition of DNA Methylation and Histone Deacetylation Prevents Murine Lung Cancer. In: Cancer Research. 2003 ; Vol. 63, No. 21. pp. 7089-7093.
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