In conclusion, we find that the HPV E6 protein uses the E6-USP46-Cdt2-Set8 pathway to effect epigenetic and gene expression changes in HPV-induced cervical cancers and cell line (Figure 6), that the E6 substitutes for the critical role of UAF1 in activating the USP46 deubiquitinase, and that specific regions of Cdt2 are necessary for its stabilization by E6-USP46, ruling out non-specific modes by which Cdt2 might have been deubiquitinated and stabilized. Here, USP46 is linked to cervical carcinoma.