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Inactivation of nuclear retinoic acid receptor [beta] (RAR[beta]) expression is implicated in tumorigenesis. We hypothesized that loss of RAR[beta] in gastric cancer cells may occur as a result of multiple factors, including epigenetic modifications which alter RAR[beta] promoter chromatin structure. We examined hypermethylation of CpG islands present in the RAR[beta] promoter by methylation-specific PCR and the expression of RAR[beta] 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. RAR[beta] 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 RAR[beta], whereas it was detected in 22 % (2/9) of tumors with retained RAR[beta] expression. To investigate the functions of exogenous RAR[beta] in gastric cancer cells, we transfected a retroviral RAR[beta] expression vector (LNS[beta]) into MKN-28 cells that have hypermethylation of the RAR[beta] 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 RAR[beta] 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 RAR[beta] by rendering the chromatin structure inaccessible to the transcription machinery.

(C) 2001 Blackwell Science Ltd.