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Adv cel sci tissue cul 2017 | Volume 1 Issue 2
Cell Science, Stem Cell Research &
Pharmacological Regenerative Medicine
November 29-30, 2017 | Atlanta, USA
Annual Congress on
T
he STK4-encoded MST1 (mammalian STE20-like kinase 1)
and its key intermediate LATS1/2 (large tumor suppressor
1 and 2) are core components of the Hippo pathway in
mammalian. The transcriptional co-activator YAP1/WWTR1
(thereof YAP) is a prominent nuclear effector of the Hippo
pathway, which restricts organ size and tumorigenesis. The
MST1 and LATS1/2 signaling cascade phosphorylates and
inhibits YAP. Evidence suggests that activation of YAP is
linked to poor cancer prognosis. Our studies have indicated
that dysregulation of the MST1-YAP1 axis plays critical role
in the etiology of metastatic prostate cancer (PC). However,
the mechanism of how the MST1-YAP axis contributes to
aggressive PC remains elusive. Here, we tested a novel
concept that MST1 low cell variants that share cancer stem-
like cells (CSCs) and epithelial-to-mesenchymal transition
(EMT) phenotypes leads to metastatic PC through increases
in interaction of nuclear YAP1 with androgen receptor (AR),
a key oncogene for PC. Using our prior knowledge, we
developed a novel method to isolate MST1 low and MST1
high cell variants to test this concept. Our functional and
molecular analysis demonstrated that unlike MST1 high,
MST1 low cells expressed the high levels of CSCs and EMT
markers and were resistant to enzalutamide (ENZ), a direct
small molecule inhibitor of AR signaling. In addition, MST1
low cells were highly invasive
ex vivo
and
in vivo
compared
with MST1 high cells. Moreover, we demonstrated that
nuclear YAP1 interacted with AR and that the interaction
between YAP and AR occurred independently of androgen
hormone signaling and were resistant to ENZ exposure in
castration-resistant PC cells in comparison with castration-
sensitive PC cells. Furthermore, we demonstrated that
silencing of MST1 increased stem cell characteristics as well
augmented androgen-independent YAP-AR interactions
and PC cell growth
ex vivo
. In addition, MST1 induction had
the opposite effects, validating our above observations.
In summary, these findings suggest that the STK4/Hippo-
YAP signaling axis plays a critical role in the promotion of
metastatic disease and targeting of this pathway could reveal
a new approach to fight against invasive cancer.
Speaker Biography
Bekir Cinar has completed his Post-doctoral Fellowship, Boston Children’s Hospital,
Harvard Medical School (HMS), Boston, MA (2002-2006) and PhD from Department
of Biochemistry and Molecular Genetics, School of Medicine University of Virginia,
Charlottesville, VA (1995-2002), DVM Veterinary Medical School, Ankara University,
Ankara,Turkey(1987-1992).Currently,he isworkingasAssociateProfessor,Department
of Biological Sciences, Clark Atlanta University (CAU), Atlanta, GA (2015 to present).
Presently, he is also member of the Center for Cancer Research and Therapeutic
Development at CAU and a member of the NCI-designated Winship Comprehensive
Cancer Center at Emory University. Prior to joining CAU, he was Assistant Professor
of Medicine-Hematology/Oncology and Biomedical Sciences at Cedars-Sinai Medical
Center, where he was a member of Samuel Oschin Comprehensive Cancer Institute.
e:
bcinar@cau.eduBekir Cinar
Clark Atlanta University, USA
The STK4/Hippo-YAP axis promotes metastasis by increasing cancer cell
stemness