CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16(INK4) protein induction by 5-aza 2'deoxycytidine

G. A. Otterson, S. N. Khleif, W. Chen, A. B. Coxon, F. J. Kaye

Research output: Contribution to journalArticle

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Abstract

Absent expression of the cyclin dependent kinase-inhibitor, p16(INK4), is, observed in a wide range of primary human cancers. Although homozygous deletions and point mutations have been reported in a subset of these tumors, the molecular basis for absent p16(INK4) in other samples is unknown. We have examined 33 tumor cell lines and have shown that hypermethylation of a G:C-rich region within exon 1 of the CDKN2 gene was present in 100% of samples with wildtype RB expression and no detectable CDKN2 mutations. Treatment for at least 4 hours with the demethylating agent 5-aza 2'deoxycytidine, but not 5-azacytidine or 6-azacytidine, induces the prolonged expression of p16(INK4) protein in each of these samples following a discrete 24-48 hour lag period. Consistent with the hypothesis that hypermethylation of the CDKN2 gene is a tumor-specific mechanism for gene inactivation, we observed hypomethylation at the exon 1 site exclusively in tumor lines that expressed p16(INK4) or that had sustained inactivating point mutations within the CDKN2 open reading frame. These findings demonstrate a link between DNA methylation and the p16(INK4):RB tumor suppressor pathway.

Original languageEnglish (US)
Pages (from-to)1211-1216
Number of pages6
JournalOncogene
Volume11
Issue number6
StatePublished - Jan 1 1995

Fingerprint

decitabine
p16 Genes
Gene Silencing
Lung Neoplasms
DNA
Neoplasms
Proteins
Point Mutation
Exons
Cyclin-Dependent Kinase Inhibitor p16
Azacitidine
Sequence Deletion
DNA Methylation
Tumor Cell Line
Open Reading Frames
Mutation

Keywords

  • 5-aza 2'deoxycytidine
  • CDKN2
  • Lung cancer
  • Methylation
  • p16(INK4)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Otterson, G. A., Khleif, S. N., Chen, W., Coxon, A. B., & Kaye, F. J. (1995). CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16(INK4) protein induction by 5-aza 2'deoxycytidine. Oncogene, 11(6), 1211-1216.

CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16(INK4) protein induction by 5-aza 2'deoxycytidine. / Otterson, G. A.; Khleif, S. N.; Chen, W.; Coxon, A. B.; Kaye, F. J.

In: Oncogene, Vol. 11, No. 6, 01.01.1995, p. 1211-1216.

Research output: Contribution to journalArticle

Otterson, GA, Khleif, SN, Chen, W, Coxon, AB & Kaye, FJ 1995, 'CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16(INK4) protein induction by 5-aza 2'deoxycytidine', Oncogene, vol. 11, no. 6, pp. 1211-1216.
Otterson, G. A. ; Khleif, S. N. ; Chen, W. ; Coxon, A. B. ; Kaye, F. J. / CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16(INK4) protein induction by 5-aza 2'deoxycytidine. In: Oncogene. 1995 ; Vol. 11, No. 6. pp. 1211-1216.
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