Trichostatin A up-regulates human papillomavirus type 11 upstream regulatory region-E6 promoter activity in undifferentiated primary human keratinocytes

Human papillomavirus (HPV) gene expression in squamous epithelia is differe ntiation dependent in benign patient lesions and in organotypic raft cultur es of primary human keratinocytes (PHKs). Using the lacZ reporter in raft c ultures, we previously showed that this transcriptional regulation of the H PV type 11 (HPV-11) enhancer-promoter located in the upstream regulatory re gion (URR) appears to have resulted from coordination between the transcrip tion transactivators AP1, Oct1, and Spl in differentiated upper strata and the repressor C/EBP in proliferating basal cells. We report here that trich ostatin A, a specific inhibitor of histone deacetylase, dramatically stimul ated reporter gene activity from the wild-type HPV-11 URR or the C/EBP muta tion in PHKs grown in undifferentiated submerged cultures. In epithelial ra ft cultures, upregulation occurred predominantly in basal and parabasal str ata; this effect was promoter specific, as expression of the lacZ reporter gene driven by the murine leukemia virus long terminal repeat (LTR), the ke ratin 14 promoter, or the involucrin promoter was not altered, nor was expr ession of endogenous keratin 10 and profilaggrin affected. However, the res ponses were not cell type or species specific, as identical results were ob served for both HPV-11 URR-lacZ and LTR-lacZ in murine retrovirus producer cell lines of fibroblast origin.