Gene promoter methylation causes loss of tumor suppressor genes function in human
cancer. Here, we show that the CDH4 gene, a member of the
cadherin family encoding for
R-cadherin, contains a CpG island located at the 5' of the first exon, which functions as a promoter
element and is frequently affected by methylation in human
cancer. By using methylation-specific PCR and reverse transcription-PCR in human
cancer cell lines, promoter methylation could be directly linked to loss of gene expression.
After treatment with the demethylating agent 5-aza-2-deoxycytidine, expression could be restored. Analysis of human primary
tumors revealed that the CDH4 gene is methylated in 78% (38 of 49) of colorectal and 95% (20 of 21) of gastric
carcinomas. CDH4 methylation was not detected in nonneoplastic colonic (0 of 10) and stomach (0 of 10) tissues or in peripheral blood (0 of 17). CDH4 methylation was detected in histologically normal tissues located in proximity of the
neoplasms, indicating that CDH4 methylation is an early event in gastrointestinal
tumor progression. We also proved that CDH4 methylation can be revealed in the peripheral blood of
cancer patients. Our results indicate that CDH4 may act as a tumor suppressor gene in human gastrointestinal
tumors and can potentially be used as an early diagnostic marker for gastrointestinal
tumorigenesis.