Overexposure of the human skin to solar ultraviolet (UV) radiation is the major 
etiologic factor for development of skin cancers. Here, we report the results of 
epigenetic modifications in UV-exposed skin and skin tumors in a systematic 
manner. The skin and tumor samples were collected after chronic exposure of the 
skin of SKH-1 hairless mice to UVB radiation using a well-established 
photocarcinogenesis protocol. We found a distinct DNA hypermethylation pattern 
in the UVB-exposed epidermal skin and UVB-induced skin tumors that was 
associated with the elevated expression and activity of the DNA 
methyltransferases (Dnmt) 1, Dnmt3a and Dnmt3b. To explore the role of 
hypermethylation in skin photocarcinogenesis, we focused on the p16(INK4a) and 
RASSF1A tumor suppressor genes, which are transcriptionally silenced on 
methylation. We established that the silencing of these genes in UVB-exposed 
epidermis and UVB-induced skin tumors is associated with a network of epigenetic 
modifications, including hypoacetylation of histone H3 and H4 and increased 
histone deacetylation, as well as recruitment of methyl-binding proteins, 
including MeCP2 and MBD1, to the methylated CpGs. Higher levels of DNA 
methylation and DNMT activity in human squamous cell carcinoma specimens than in 
normal human skin suggest that the data are relevant clinically. Our data 
indicate for the first time that UVB-induced DNA hypermethylation, enhanced Dnmt 
activity and histone modifications occur in UVB-exposed skin and UVB-induced 
skin tumors and suggest that these events are involved in the silencing of tumor 
suppressor genes and in skin tumor development.