VILIP-1 downregulation in non-small cell lung carcinomas: Mechanisms and prediction of survival

Jian Fu, Kathryn Fong, Alfonso Bellacosa, Eric Ross, Sinoula Apostolou, Daniel E. Bassi, Fang Jin, Jirong Zhang, Paul Cairns, Inmaculada Ibañez de Caceres, Karl Heinz Braunewell, Andres J. Klein-Szanto

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

VILIP-1, a member of the neuronal Ca++ sensor protein family, acts as a tumor suppressor gene in an experimental animal model by inhibiting cell proliferation, adhesion and invasiveness of squamous ceil carcinoma cells. Western Blot analysis of human tumor cells showed that VILIP-1 expression was undetectable in several types of human tumor cells, including 11 out of 12 non-small cell lung carcinoma (NSCLC) cell lines. The down-regulation of VILIP-1 was due to loss of VILIP-1 mRNA transcripts. Rearrangements, large gene deletions or mutations were not found. Hypermethylation of the VILIP-1 promoter played an important role in gene silencing. In most VILIP-1-silent cells the VILIP-1 promoter was methylated. In vitro methylation of the VILIP-1 promoter reduced its activity in a promoter-reporter assay. Transcriptional activity of endogenous VILIP-1 promoter was recovered by treatment with 5′-aza-2′-deoxycytidine (5′-Aza-dC). Trichostatin A (TSA), a histone deacetylase inhibitor, potently induced VILIP-1 expression, indicating that histone deacetylation is an additional mechanism of VILIP-1 silencing. TSA increased histone H3 and H4 acetylation in the region of the VILIP-1 promoter. Furthermore, statistical analysis of expression and promoter methylation (n=150 primary NSCLC samples) showed a significant relationship between promoter methylation and protein expression downregulation as well as between survival and decreased or absent VILIP-1 expression in lung cancer tissues (p<0.0001). VILIP-1 expression is silenced by promoter hypermethylation and histone deacetylation in aggressive NSCLC cell lines and primary tumors and its clinical evaluation could have a role as a predictor of short-term survival in lung cancer patients. Copyright:

Original languageEnglish
Article numbere1698
Pages (from-to)e1698
JournalPLoS ONE
Volume3
Issue number2
DOIs
StatePublished - Feb 27 2008

Keywords

  • Carcinoma, Non-Small-Cell Lung/diagnosis
  • DNA Methylation
  • Down-Regulation/genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Histones/metabolism
  • Humans
  • Neurocalcin/genetics
  • Promoter Regions, Genetic
  • RNA, Messenger/genetics
  • Survival Rate

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