Downregulation of the expression of major histocompatibility complex class I antigens on the surface of high-risk HPVs-transformed cells may contribute to their high tumorigenic potential, which enables them to escape immune recognition by cytotoxic T lymphocytes. In this study, we show that the viral E7 oncoprotein mediates transcriptional downregulation of the major histocompatibility complex (MHC) class I genes by targeting the class I promoter in HPV16 containing CaSki tumor cells. Using the chromatin immunoprecipitation assay, we demonstrated that HPV16E7 and specific HADCs, including HADC1, HADC2, and HADC8, are physically associated with the class I promoter and the historic of the class I promoter was deacetylated. Knocking down of HPV16E7 expression with the E7-specific small interfering RNA induced the release of HPV17E7 as well as HDAC1 and HDAC2 from the class I promoter. Furthermore, HPV16E7 siRNA resulted in a dramatic increase in histone acetylation. Importantly, MHC class I antigen expression was up-regulated on the surface of cells transfected with the E7 siRNA, but not on that of untransfected cells. Taken together, our results demonstrate that the HPV16E7 protein is associated with the MHC class I promoter and mediates MHC class I downregulation by repressing chromatin activation. (c) 2006 Elsevier Inc. All rights reserved.