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 had recently linked E6AP HPV-independent cancer. We previously discovered that E6AP regulates the turnover of the tumour suppressor PML [1]. Recently, we have shown that elevation of E6AP and downregulation of PML occurs in human prostate cancer, and predicts poor survival [2]. To investigate the role of E6AP in prostate cancer we have knocked down (KD) its expression in prostate cancer cell lines. We found that KD of E6AP is sufficient to inhibit the growth of PC cells in vitro 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/IL2rγ null (NSG) mice. Consistent with previous results we found that E6AP KD significantly attenuate tumour growth in vivo. Also, in the TRAMP mouse model for PC the loss of a single E6AP allele was sufficient to attenuate median latency of tumour growth by 50 days.
Taken together, we have demonstrated a role for E6AP in the growth and survival of PC cells and in the development of PC in vitro and in vivo. Thus, our results suggest that inhibition of E6AP and restoration of PML may serve as a novel approach for the treatment of prostate cancer.
References:
1. Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, et al., E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ. 2009; 16(8): 1156-66.
2. S. E. Birch, et al., Expression of E6AP and PML predicts for prostate cancer progression and cancer-specific death. Ann. Oncol.2014 Sep 17.