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

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

Research output: Contribution to journalArticle

225 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16(INK4) protein induction by 5-aza 2'deoxycytidine'. Together they form a unique fingerprint.

  • 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.