Certain cutaneous human papilloma viruses (HPVs) which belong to the β-PV genus have been associated with the development of non-melanoma skin cancer (NMSC). The mechanisms by which the viruses contribute to the of skin cancer are presently being investigated. Our previous studies showed that E6 protein of HPV16, a mucosal α HPV type, is capable to cooperate with the ubiquitin ligase E6AP, to enhance the oncogenic Wnt/β-catenin pathway. HPV16 E6 increased Wnt/β-catenin signaling by both stimulation and augmentation of the signal, through different mechanisms. In the present study we investigated the ability of E6 proteins of several β and α cutaneous HPV types to potentiate Wnt signaling. We show that E6 proteins from cutaneous β (8, 24, 38, 49) and α (10) HPV types were capable to augment Wnt signaling. E6AP increased the activity of E6 by stabilizing the E6 proteins. Both wild type and mutant E6AP that lacks the ubiquitin ligase activity were capable to stabilize E6 and augment Wnt/β-catenin transcription. The ability of E6AP to elevate β-catenin/TCF transcription correlated with the ability of E6AP to associate with E6, showing higher ability with the α E6 proteins. The E6 proteins of the cutaneous HPVs were also capable to stimulate Wnt signaling. The stimulation was associated with stabilization of β-catenin with the α types exhibiting higher activity in stabilization of β-catenin and stimulation of Wnt/β-catenin transcription. This study revealed the role of cutaneous HPV types in potentiating the Wnt/β-catenin signaling pathway which may contribute to skin carcinogenesis.
