Inactivation of retinoic acid receptor β by promoter CpG hypermethylation in gastric cancer

K. Hayashi, H. Yokozaki, S. Goodison, N. Oue, T. Suzuki, R. Lotan, W. Yasui, E. Tahara

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Inactivation of nuclear retinoic acid receptor β (RARβ) expression is implicated in tumorigenesis. We hypothesized that loss of RARβ in gastric cancer cells may occur as a result of multiple factors, including epigenetic modifications which alter RARβ promoter chromatin structure. We examined hypermethylation of CpG islands present in the RARβ promoter by methylation-specific PCR and the expression of RARβ in gastric cancer cell lines and tissues. Three (MKN-28, -45 and -74) out of eight gastric cancer cell lines had a loss of RAR expression associated with promoter methylation. RARβ expression was retrieved in these cell lines by treatment with 5-azacytidine or by the histone deacetylase inhibitor trichostatin A. Promoter hypermethylation was detected in 64% (7/11) of gastric carcinoma tissues with reduced expression of RARβ, whereas it was detected in 22% (2/9) of tumors with retained RARβ expression. To investigate the functions of exogenous RARβ in gastric cancer cells, we transfected a retroviral RARβ expression vector (LNSβ) into MKN-28 cells that have hypermethylation of the RARβ promoter. Overexpression of RAR in MKN-28 cells appeared to regulate the expression of DNA methyltransferase and DNA demethylase and the acetylation of hitone H4. These results suggest that the transcriptional inactivation of the RARβ by promoter CpG hypermethylation is frequently associated with gastric carcinoma. Our data also suggests that DNA methylation plays a pivotal role in establishing and maintaining an inactive state of RARβ by rendering the chromatin structure inaccessible to the transcription machinery.

Original languageEnglish (US)
Pages (from-to)13-21
Number of pages9
JournalDifferentiation
Volume68
Issue number1
DOIs
StatePublished - 2001

Keywords

  • 5-azacytidine
  • Partial methylation
  • Retinoic acid receptor-β
  • TSA

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology
  • Cancer Research

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