Coxsackie and adenovirus receptor (CAR) is not only a high-affinity receptor for adenovirus, but also a tumor inhibitor in both prostate and bladder cancer lines. Decreased CAR gene expression is often detected in cancer specimens; however, the mechanism(s) is still unknown. In this study, we cloned the entire CAR gene and characterized the core promoter sequence of the CAR gene. The CAR gene promoter activity correlated with the differential expression of CAR mRNA levels from several urogenital cancer cell lines, indicating that the down-regulation of CAR gene expression is mediated by transcriptional regulation. It is known that epigenetic control, such as DNA methylation and histone acetylation of chromatin structure, dictates gene expression. Data from this study indicate that the activation of the CAR gene promoter is modulated by histone acetylation, but not by DNA methylation, in urogenital cancer cells. Also, a potent cancer chemotherapeutic agent (FR901228), a histone deacetylase inhibitor, was able to induce endogenous CAR gene expression in several urogenital cancer cells. Taken together, epigenetic control of CAR gene underlies the down-regulation of this gene in urogenital cancers.