Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells

Kazuyasu Kobayashi, Mamoru Oouchida, Toshiya Tsuji, Hiroko Hanafusa, Masahiro Miyazaki, Masayoshi Namba, Nobuyoshi Shimizu, Kenji Shimizu

Research output: Contribution to journalArticle

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Abstract

The human REIC gene is a recently found mortalization-related gene and a candidate tumor suppressor gene expression of which is largely attenuated in many immortalized and tumor-derived cell lines (Biochem. Biophys. Res. Commun. 268 (2000) 20-24). To gain insight into the mechanisms of the down-regulation, we investigated the genomic structure and promoter activity of the human REIC gene. The gene, identical with the DKK-3 gene, resides on chromosome 11p15.1, consists of nine exons, and has two promoters. Methylation in the main promoter region was detected in 11 out of 21 cell lines tested (52%) derived from a variety of human tumors, in which the expression of the REIC gene was decreased. In ten of these 11 cell lines the minor promoter was also methylated. Similarly, the REIC gene expression was decreased in 14 of 24 fresh non-small cell lung cancer specimens (58%) compared to that in corresponding non-cancerous tissue, though allelic loss and tumor-specific mutation were rare. Of these 14 tumors, at least five tumors exhibited heavy methylation of the REIC promoter region. These results indicate that the down-regulation of the REIC gene expression is ascribed to the aberrant promoter hyper-methylation at least in a subset of human tumors. The expression was restored upon treatment of SQ5 cells with 5-aza-deoxycytidine, confirming DNA methylation as the mode of downregulation. A notable single nucleotide polymorphism in the coding region (cSNP) with an amino acid substitution of glycine (GGG) to arginine (AGG) was found at codon 335 of the REIC gene. However, the distribution of the cSNP showed no significant difference between lung cancer patients and healthy population.

Original languageEnglish
Pages (from-to)151-158
Number of pages8
JournalGene
Volume282
Issue number1-2
DOIs
Publication statusPublished - Jan 9 2002

Fingerprint

Methylation
Genes
Neoplasms
Down-Regulation
Gene Expression
Genetic Promoter Regions
Cell Line
Deoxycytidine
Loss of Heterozygosity
Gene Expression Regulation
DNA Methylation
Amino Acid Substitution
Tumor Cell Line
Tumor Suppressor Genes
Human Activities
Non-Small Cell Lung Carcinoma
Codon
Glycine
Single Nucleotide Polymorphism
Arginine

Keywords

  • Down-regulation
  • Gene expression
  • Immortalization
  • Lung cancer
  • Promoter-methylation
  • Single nucleotide polymorphism in coding region

ASJC Scopus subject areas

  • Genetics

Cite this

Kobayashi, K., Oouchida, M., Tsuji, T., Hanafusa, H., Miyazaki, M., Namba, M., ... Shimizu, K. (2002). Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells. Gene, 282(1-2), 151-158. https://doi.org/10.1016/S0378-1119(01)00838-1

Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells. / Kobayashi, Kazuyasu; Oouchida, Mamoru; Tsuji, Toshiya; Hanafusa, Hiroko; Miyazaki, Masahiro; Namba, Masayoshi; Shimizu, Nobuyoshi; Shimizu, Kenji.

In: Gene, Vol. 282, No. 1-2, 09.01.2002, p. 151-158.

Research output: Contribution to journalArticle

Kobayashi, K, Oouchida, M, Tsuji, T, Hanafusa, H, Miyazaki, M, Namba, M, Shimizu, N & Shimizu, K 2002, 'Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells', Gene, vol. 282, no. 1-2, pp. 151-158. https://doi.org/10.1016/S0378-1119(01)00838-1
Kobayashi, Kazuyasu ; Oouchida, Mamoru ; Tsuji, Toshiya ; Hanafusa, Hiroko ; Miyazaki, Masahiro ; Namba, Masayoshi ; Shimizu, Nobuyoshi ; Shimizu, Kenji. / Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells. In: Gene. 2002 ; Vol. 282, No. 1-2. pp. 151-158.
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abstract = "The human REIC gene is a recently found mortalization-related gene and a candidate tumor suppressor gene expression of which is largely attenuated in many immortalized and tumor-derived cell lines (Biochem. Biophys. Res. Commun. 268 (2000) 20-24). To gain insight into the mechanisms of the down-regulation, we investigated the genomic structure and promoter activity of the human REIC gene. The gene, identical with the DKK-3 gene, resides on chromosome 11p15.1, consists of nine exons, and has two promoters. Methylation in the main promoter region was detected in 11 out of 21 cell lines tested (52{\%}) derived from a variety of human tumors, in which the expression of the REIC gene was decreased. In ten of these 11 cell lines the minor promoter was also methylated. Similarly, the REIC gene expression was decreased in 14 of 24 fresh non-small cell lung cancer specimens (58{\%}) compared to that in corresponding non-cancerous tissue, though allelic loss and tumor-specific mutation were rare. Of these 14 tumors, at least five tumors exhibited heavy methylation of the REIC promoter region. These results indicate that the down-regulation of the REIC gene expression is ascribed to the aberrant promoter hyper-methylation at least in a subset of human tumors. The expression was restored upon treatment of SQ5 cells with 5-aza-deoxycytidine, confirming DNA methylation as the mode of downregulation. A notable single nucleotide polymorphism in the coding region (cSNP) with an amino acid substitution of glycine (GGG) to arginine (AGG) was found at codon 335 of the REIC gene. However, the distribution of the cSNP showed no significant difference between lung cancer patients and healthy population.",
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