Promoter hypomethylation of a novel cancer/testis antigen gene CAGE is correlated with its aberrant expression and is seen in premalignant stage of gastric carcinoma

Bomsoo Cho, Hansoo Lee, Shin Wu Jeong, Yung Jue Bang, Hyun Joo Lee, Kyu Sang Hwang, Hae Yeong Kim, Yun Sil Lee, Gyeong Hoon Kang, Doo Il Jeoung

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118 Scopus citations

Abstract

Previously, we reported the identification and characterization of a novel cancer/testis antigen gene, CAGE4, that was expressed in various histological types of tumors, but not in normal tissues, with the exception of the testis. To date, molecular mechanisms for the expression of CAGE have never been studied. In our expression analysis, we found that some cancer cell lines did not express CAGE. The expression of CAGE could be restored in these cell lines by treatment with 5′-aza-2′-deoxycytidine, suggesting that the expression of CAGE is mainly suppressed by hypermethylation. Bisulfite sequencing analysis of the 16 CpG sites of the CAGE promoter in various cancer cell lines and tissues revealed a close relationship between the methylation status of the CAGE promoter and the expression of CAGE. The transient transfection experiments displayed that the methylation of CpG sites inhibited the CAGE promoter activity in luciferase reporter assays. The methylation of the CpG sites inhibited the binding of transcription factors, shown by a mobility shift assay. A methylation-specific PCR analysis revealed that hypomethylation of the CAGE promoter was present at frequencies of more than 60% in breast, gastric, and lung cancers, and hepatocellular carcinomas, and at frequencies of less than 40% in prostate, uterine cervical, and laryngeal cancers. Promoter hypomethylation was found in chronic gastritis (19/55, 34.5%) and liver cirrhosis (13/22, 59%), but not in normal prostate, normal colon, or chronic hepatitis. These results suggest that the methylation status of the CpG sites of CAGE determines its expression, that the hypomethylation of CAGE precedes the development of gastric cancer and hepatocellular carcinoma, and that the high frequencies of hypomethylation of CAGE, in various cancers would be valuable as a cancer diagnostic marker.

Original languageEnglish
Pages (from-to)52-63
Number of pages12
JournalBiochemical and Biophysical Research Communications
Volume307
Issue number1
DOIs
StatePublished - 18 Jul 2003

Keywords

  • CAGE
  • Hypomethylation
  • Methylation-specific PCR
  • Transcription

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