E3 ubiquitin ligase E6AP plays an essential role in the progress and development of various cancers. To explore the mechanism of E6AP in liver cancer, we performed proteomic analysis with E6AP knockdown and negative control HepG2 cells. We identified proteins were significantly regulated upon knockdown of E6AP. Pathway analysis confirmed the known phenotypic effect of E6AP. Overall, results from our investigation provide potential biological pathways and target genes controlled by E6AP in liver cancer cells.