Update datafiles E3 ubiquitin ligase E6AP and histone deacetylase HDAC6 play essential roles in the progress and development of various cancers. To explore the mechanism of E6AP and HDAC6 in liver cancer, we performed proteomic analysis with E6AP knockdown, HDAC6 knockdown and negative control HepG2 cells. We identified proteins were significantly regulated upon knockdown of E6AP or HDAC6. Pathway analysis confirmed the known phenotypic effect of E6AP and HDAC6. Overall, results from our investigation provide potential biological pathways and target genes controlled by E6AP and HDAC6 in liver cancer cells.