As a nuclear phosphoprotein, proto-oncogene protein DEK is capable to changing chromatin structure. DEK was recently identified as an inhibitor of histone acetylation mediated by p300 and PCAF and to facilitate transcriptional repression. To elucidate the biological functions of DEK in vivo, we have constructed transgenic flies that overexpress the human DEK in the developing eye. Transgenic flies developed a severe rough eye phenotype, which is indicative of ectopically induced apoptosis. Genetic and biochemical analyses, including the rescue of the apoptotic phenotype by pan-caspase inhibitor protein p35 and caspase activity analyses, suggested that DEK induces apoptotic cell death through a caspases-9 and -3 dependent pathway. Using extracts from larval salivary glands, we have determined that the global histone acetylation levels of histone H3 Lys9 and H4 Lys5 were decreased upon DEK overexpression. Using chromatin immunoprecipitation assays, we have demonstrated that overexpression of DEK induced the histone H3 and H4 hypoacetylation of promoter of the antiapoptotic gene bcl-2. Co-expression of bcl-2 also rescued apoptosis and the reduced expression of bcl-2 gene was analyzed by real-time PCR. Our results indicate that acidic domain containing protein DEK might have a role in modulating both transcriptional regulation and apoptosis through HAT inhibitory activity. J. Cell. Biochem. 103: 1283–1293, 2008. © 2007 Wiley-Liss, Inc.