Identification of anti-apoptotic AREL1 E3 ubiquitin ligase as a novel oncogene that promotes tumor angiogenesis via HIF-1

25^th WORLD CANCER CONFERENCE

October 19-21, 2017 | Rome, Italy

Deug Y Shin, Taeheun Oh and Jung-bin Kim

Dankook University, South Korea

Posters & Accepted Abstracts: J Cancer Sci Ther

Abstract :

We previously reported the anti-apoptosis functions of a novel anti-apoptotic E3 ubiquitin ligase, AREL1, which ubiquitinates and promotes the proteasome-dependent degradation of cytosolic forms of IAP antagonists. In the present study, we identified AREL1 as an oncogene that targets PHD2. Elevated expression of AREL1 was detected in 65% of randomly selected human lung and colon cancer cell lines and also found in 42% of 424 human tumor tissues. Furthermore, AREL1trangenic mice enhanced chemical-induced carcinogenesis as compared to wild-type ones. The oncogenic function of AREL1 led us to screen AREL1 target proteins involving in oncogenesis. PHD2, which regulates angiogenesis and tumor development, was identified as an AREL1-interacting protein from a yeast two-hybrid screen. PHD2 was down-regulated by AREL1. This down-regulation was blocked by either a potent proteasome inhibitor, MG132 or expression of an E3 activity-deficient mutant form of AREL1, AREL1-A790A. Taken together with that ubiquitination of endogenous PHD2 was enhanced by AREL1, these results indicate that AREL1 ubiquitinates and promotes a proteasome-dependent degradation of PHD2. Tumor angiogenesis of xenograft of AREL1-expressing cells was enhanced in association with down-regulation of PHD2 and up-regulation of HIF-1. Furthermore, endothelial cell tube formation assay revealed enhanced release of pro-angiogenic factors from AREL1expressing cells. Therefore, these results suggest that elevated expression of AREL1 contributes to tumorigenesis through targeting PHD2 as well as IAP antagonists, thus blocking apoptosis and enhancing angiogenesis.