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Allied Journal of Medical Research
|
Volume 2
Page 24
Note:
allied
academies
CANCER THERAPY AND ONCOLOGY
NEUROLOGY AND BRAIN DISORDERS
&
International Conference on
International Conference on
J u n e 2 1 - 2 2 , 2 0 1 8 | O s a k a , J a p a n
Joint Event on
DEAD-BOX RNA HELICASE DP103
ENHANCES YAP SUMOYLATION FOR
YAP-TEAD DEPENDENCE AND STATIN
SENSITIVITY IN TRIPLE NEGATIVE BREAST
CANCER
Alan Prem Kumar
Cancer Science Institute of Singapore - National University of Singapore, Singapore
S
imvastatin, a lipophilic statin used for lowering cholesterol, inhibits
3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the key enzyme
of the mevalonate pathway. Studies have shown that cancer cells express
deregulated level of HMGCR and statins exert anti-tumoral activities.
We first assessed correlation between mevalonate pathway genes and
DDX20 (DP103, Gemin-3) in 1325 breast cancer patients and observed a
positive correlation between DDX20 and the mevalonate pathway genes.
Having this data, we then proceeded to explore the effect of statins on
DDX20 expression. We used various
in vitro
cell lines and
in vivo
statin
clinical trial patients’ specimens, mouse xenograft, mouse intravenous
tail injection and Drosophila (wild-type vs Gemin-3 knockdown vs Gemin-3
overexpression flies) models. We show exposure to statin decreases
the expression of DDX20. Through a series of add-back experiments,
we show that the decrease in DDX20 expression by statins is via the
mevalonate pathway and downstream of RhoA. In clinical specimens,
we observed breast cancer patients with high baseline DDX20 positively
correlates with high baseline YAP-TEAD expression. Having known that
SUMOylation of YAP maintains its activity and that DDX20 is a critical
enhancer of the SUMOlyation machinery, we showed through a series of
experiments that a physical interaction between DDX20 and YAP is crucial
for maintaining SUMOylation of YAP; thereby decreasing its ubiquitination
and degradation. Interestingly, we also identified for the first time that
DDX20 is a direct target of YAP-TEAD complex and that maintenance of
DDX20 expression is needed as a positive feedback forming an Achilles
heel for sustained YAP-TEAD activity.
Alan Prem Kumar has completed PhD from Uni-
versity of North Texas, USA. He is currently an
Assistant Professor at the National University
of Singapore. He has over 150 publications that
and his publication H-index is 36 and has been
serving as an editorial board member of reput-
ed Journals and established several industry
collaborations.
csiapk@nus.edu.sgBIOGRAPHY
Alan Prem Kumar, Allied J Med Res 2018, Volume 2