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Allied J Med Res 2017
Volume 1 Issue 2 Herbal Medicine 2017
September 01-02, 2017 London, UK
3rd International Conference and Expo on
Herbal & Alternative Medicine
Page 45
Transcriptional and posttranscriptional
upregulation of p27 mediates growth
inhibition of isorhapontigenin (ISO) in human
bladder cancer cells
Chuanshu Huang1 and Haishan Huang 1, 2
1New York University School of Medicine, USA
2Wenzhou Medical University, China
There are few approved drugs available for the treatment
of muscle invasive bladder cancer (MIBC). Recently,
we have demonstrated that Isorhapontigenin (ISO), a
new derivative isolated from the Chinese herb Gnetum
cleistostachyum, effectively induces cell-cycle arrest at
the G0/G1 phase and inhibits anchorage-independent cell
growth through the miR-137/Sp1/cyclin D1 axis in human
MIBC cells both in vitro and in vivo. Herein, we show that
treatment of MIBC cells with ISO resulted in a significant
upregulation of p27, a key cyclin-dependent kinase (CDK)
inhibitor. Importantly, knockdown of p27 caused a decline
in the ISO-induced G0-G1 growth arrest and reversed ISO
suppression of anchorage-independent growth in MIBC
cells. Mechanistic studies revealed that ISO promoted
p27 expression at mRNA transcription level through an
increase in the direct binding of FOXO1 to its promoter,
while knockdown of FOXO1 attenuated ISO inhibition of
MIBC cell growth. On the other hand, ISO upregulated
the 3’UTR activity of p27 which was accompanied by
a reduction of miR-182 expression. In line with these
observations, ectopic expression of miR-182 did
significantly block p27 3’UTR activity, whereas mutation
of the miR-182 binding site at p27 3’UTR effectively
reversed this inhibition and led to a significant loss of ISO
induction effect on its activity, indicating that miR-182 is
able to bind directly to p27 3’UTR and repress its activity
in MIBC cells. Accordingly, ectopic expression of miR-182
also attenuated ISO upregulation of p27 expression and
impaired ISO inhibition of BC cell growth. These studies
reveal that p27 expression is transcriptionally upregulated
by enhancing binding of FOXO1 to its promoter, and that it is
post-transcriptionally induced through decreasing binding
of miR-182 to its mRNA 3’UTR upon ISO treatment. Our
results not only provide novel insight into understanding of
the underlying mechanism related to regulation of MIBC
cell growth, they also identify a new role and mechanisms
underlying ISO inhibition of the growth.
Allied J Med Res 2017