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

Authors: Hayashi, K.; Yokozaki, H.¹; Goodison, S.²; Oue, N.¹; Suzuki, T.¹; Lotan, R.³; Yasui, W.¹; Tahara, E.

Source: Differentiation, Volume 68, Number 1, August 2001 , pp. 13-21(9)

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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.

Keywords: retinoic acid receptor-β; partial methylation; 5-azacytidine; TSA

Document Type: Research article

DOI: http://dx.doi.org/10.1046/j.1432-0436.2001.068001013.x

Affiliations: 1: First Department of PathologyHiroshima University School of Medicine1 - 2 - 3 Kasumi, Minami-ku, Hiroshima, 734 - 8551, Japan 2: University of California, San Diego, Cancer Center and Department of Pathology, 9500 Gilman Drive, MC0912, La Jolla, CA 92093 - 0912 3: Department of Thoracic/Head and Neck Medical OncologyThe University of TexasM. D. Anderson Cancer Center, Houston, Texas 77030, USA

Publication date: 2001-08-01

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

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