In Australia, prostate cancer (PC) is the most common cancer in men, and second in the general population. The E6AP, an E3 ubiquitin ligase, is recruited by the E6 protein of the high-risk types of Human Papilloma Virus (HPV) to promote p53 degradation. While the link between E6AP and cancer has been largely described in relation to HPV, our laboratory recently linked E6AP to stress response through the discovery that E6AP regulates the turnover of the tumour suppressor PML. Lately, we have shown that elevation of E6AP and downregulation of PML occurs in human prostate cancer, and predict poor survival. To establish the role of E6AP in prostate cancer we have knocked down (KD) its expression in prostate cancer cell lines. KD of E6AP is sufficient to inhibit the growth of PC cells in vitro and in vivo, and sensitize them to stress-induced cell death. To further establish these findings, we examined the effect of E6AP KD on the growth of PC xenografts in NOD/SCID/IL2rĪ³null (NSG) mice. Further, the development of PC in the TRAMP mouse model was attenuated by 50 days by a loss of a single E6AP allele. Taken together, we have demonstrated a role for E6AP in the development of PC in vitro and in vivo, and our results suggest that inhibition of E6AP may serve as a novel approach for the treatment of prostate cancer.