30 / 37
Page 85
Notes:
conferenceseries
.com
Volume 9, Issue 9 (Suppl)
J Cancer Sci Ther, an open access journal
ISSN: 1948-5956
World Cancer 2017
October 19-21, 2017
25
th
WORLD CANCER CONFERENCE
October 19-21, 2017 | Rome, Italy
J Cancer Sci Ther 2017, 9:9(Suppl)
DOI: 10.4172/1948-5956-C1-112
Identification of anti-apoptotic AREL1 E3 ubiquitin ligase as a novel oncogene that promotes tumor
angiogenesis via HIF-1
Deug Y Shin, Taeheun Oh
and
Jung-bin Kim
Dankook University, South Korea
W
e 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, AREL1-
trangenic 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 AREL1-
expressing 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.
dyshin@dankook.ac.kr