International Journal of

Molecular Sciences

Review
The Ambivalent Function of YAP in Apoptosis
and Cancer
Xianbin Zhang * , Ahmed Abdelrahman, Brigitte Vollmar and Dietmar Zechner
Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a,
18059 Rostock, Germany; [email protected] (A.A.);
[email protected] (B.V.); [email protected] (D.Z.)
* Correspondence: [email protected]; Tel.: +49-381-494-2506; Fax: +49-381-494-2502




Received: 12 October 2018; Accepted: 23 November 2018; Published: 27 November 2018


Abstract: Yes-associated protein, a core regulator of the Hippo-YAP signaling pathway, plays a vital
role in inhibiting apoptosis. Thus, several studies and reviews suggest that yes-associated protein
is a good target for treating cancer. Unfortunately, more and more evidence demonstrates that this
protein is also an essential contributor of p73-mediated apoptosis. This questions the concept that
yes-associated protein is always a good target for developing novel anti-cancer drugs. Thus, the aim of
this review was to evaluate the clinical relevance of yes-associated protein for cancer pathophysiology.
This review also summarized the molecules, processes and drugs, which regulate Hippo-YAP
signaling and discusses their effect on apoptosis. In addition, issues are defined, which should
be addressed in the future in order to provide a solid basis for targeting the Hippo-YAP signaling
pathway in clinical trials.

Keywords: Hippo; YAP; signaling pathway; cell death; autophagy; p73; cancer; therapy

1. Introduction to YAP and the Hippo Signaling Pathway

Yes-associated protein (YAP) is a core component of the Hippo signaling pathway in mammals [1].
Initially, this pathway was described to control organ size [2]. However, recently it has been discovered
that YAP is also involved in oncogenesis [3,4] as well as apoptosis [5–11]. Hence, YAP is considered to
be an emerging target to treat cancer. In mammals, multiple proteins such as the mammalian sterile
20-like kinases (MST1 and MST2, MST1/2), the large tumor suppressor kinases (LATS1 and LATS2,
LATS1/2), the yes-associated protein (YAP), the transcriptional coactivator with PDZ-binding motif
(TAZ), and the TEA domain family (TEAD1-4) transcription factors are important components of the
Hippo signaling pathway (Figure 1) [1,2,4]. In addition, other transcription factors such as runt-related
transcription factors (RUNX) and p73 are also involved in this pathway [6,12].
It has been reported that, for example, high cellular density or stimulation of G-protein-coupled
receptors can switch “ON” Hippo signaling pathway by phosphorylating MST1/2 [13,14].
Subsequently, LATS1/2 and YAP are phosphorylated, leading to YAP cytoplasmic retention (inactive)
and degradation [13,14]. In contrast, when cells are grown under conditions of low density, this
pathway is switched “OFF”, YAP can translocate to the nucleus [1,2,4,13]. Subsequently, it interacts
with TEAD transcription factors and induces the expression of several genes, such as Cyclooxygenase-2
(COX-2) [15], BIRC 5 (Survivin) [16,17], glucose-transporter 1 (Glut1) [18], and glucose-transporter 3
(Glut3) [19].
However, it also has been found that when cells suffer DNA damage stress, nuclear YAP can
interacts with p73 and enhances the transcription of pro-apoptotic genes, such as p53AIP1 [5], Bax [6,20],
DR5 [7], and PUMA [8]. Consistent with this bivalent effect on apoptosis, the role of YAP in cancer
is also contradictive. For example, several studies demonstrated that YAP is highly expressed in

Int. J. Mol. Sci. 2018, 19, 3770; doi:10.3390/ijms19123770 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2018, 19, 3770 2 of 21

pancreatic cancer and that high expression correlates with poor survival [21,22]. In addition,
Int. J. Mol. Sci. 2018, 19, x 2 of 21
recent
evidence proved that YAP promotes metastasis and proliferation of breast cancer cells [23,24] and
contributes
evidence to the poor
proved that metastasis-free survival of
YAP promotes metastasis and these patients of
proliferation [25]. Thus,
breast these
cancer studies
cells suggest
[23,24] and that
YAPcontributes
is involved to the poor metastasis-free
in oncogenesis. survival
However, of these
Yuan et al.patients
found [25].
thatThus,
YAP these studies
is barely suggest that
expressed in human
YAPcancer
breast is involved
tissue in and
oncogenesis. However, Yuan
can be considered to beet aal.tumor
found suppressor
that YAP is barely
[26]. expressed
Therefore,inithuman
seems to be
breastdependent,
context cancer tissue and can
if YAP canbeserve
considered to be suppressor
as a tumor a tumor suppressor [26]. Therefore, it seems to be
or an oncogene.
context dependent, if YAP can serve as a tumor suppressor or an oncogene.
Thus, in this review, we summarized the clinical relevance of YAP for cancer pathophysiology.
Thus, in this review, we summarized the clinical relevance of YAP for cancer pathophysiology.
We also reviewed molecules, processes and drugs, which are involved in Hippo-YAP signaling and
We also reviewed molecules, processes and drugs, which are involved in Hippo-YAP signaling and
their effect
their onon
effect apoptosis.
apoptosis.Finally,
Finally, we definedissues
we defined issueswhich
which should
should be addressed
be addressed in theinfuture.
the future.

Figure
Figure 1. 1. Components of
Components of the
the Hippo-YAP
Hippo-YAPsignaling
signaling pathway. When
pathway. the pathway
When is switched
the pathway “ON” “ON”
is switched
(blue background), activated mammalian sterile 20-like kinases (MST1 and
(blue background), activated mammalian sterile 20-like kinases (MST1 and MST2, MST1/2)MST2, MST1/2) and and
Salvador homolog 1 (SAV1) phosphorylate and activate the large tumor suppressor kinases (LATS1
Salvador homolog 1 (SAV1) phosphorylate and activate the large tumor suppressor kinases (LATS1
and LATS2, LATS1/2). The activated LATS1/2 and MOB kinase activators 1 (MOB1) phosphorylate
and LATS2, LATS1/2). The activated LATS1/2 and MOB kinase activators 1 (MOB1) phosphorylate
yes-associated protein (YAP) or the transcriptional coactivator with PDZ-binding motif (TAZ),
yes-associated protein (YAP) or the transcriptional coactivator with PDZ-binding motif (TAZ), leading
leading to YAP/TAZ cytoplasmic retention (inactive) and degradation. When the pathway is switched
to YAP/TAZ
“OFF” (gray cytoplasmic
background), retention
YAP/TAZ (inactive) and degradation.
accumulates in the nucleus When the pathway
and forms complexesiswith
switched
some “OFF”
(gray background),
transcription YAP/TAZ
factors such as accumulates
TEA domainin the nucleusfamily
(TEAD) and forms complexes
transcription with some
factors, transcription
runt-related
factors such as factors
transcription TEA domain
(RUNX) (TEAD) family Increase
and p73. Arrow: transcription factors, runt-related transcription factors
(RUNX) and p73. Arrow: Increase.
Int. J. Mol. Sci. 2018, 19, 3770 3 of 21

2. The Anti-Apoptotic Function of YAP

2.1. YAP Is Overexpressed in Cancer and Inhibits Apoptosis

Most clinical studies have demonstrated that YAP is overexpressed in tumors and associated
with poor survival of patients with solid tumors [21,22,27], such as lung tumors [28], pancreatic
tumors [21,22,27], and colorectal tumors [29]. In addition, several studies proved that the YAP gene is
amplified in cervical, ovarian, and fallopian tube cancers [30,31]. Moreover, silencing the expression of
YAP gene by shRNA [18,32,33] or siRNA [15,34–48] could induce apoptosis (Table 1). Consistent with
this finding, overexpressing YAP significantly inhibited apoptosis of liver [38,49,50], pancreas [39],
colorectal cancer [15,51], and lung cancer cells [52]. All these publications suggest that YAP inhibits
apoptosis. This could lead to accelerated tumor growth, which might then cause poor survival of
patients [53]. Thus, YAP has a pro-oncogenic function. However, Liu et al. found that YAP gene
silencing failed to promote cell apoptosis in thyroid papillary carcinoma cells [54]. In addition, they
demonstrated that YAP gene silencing inhibited c-Myc expression. Possibly the repression of the
pro-apoptotic gene c-Myc prevented the induction of apoptosis in these cells [55]. This might explain
why silencing the YAP gene failed to induce apoptosis in this study [54].

Table 1. Manipulation of YAP expression and its effect on apoptosis.

Cancer Method YAP Expression Apoptosis PMID

Esophagus shRNA 27307755 [32]
Lung shRNA 25665005 [33]
Breast shRNA 28892790 [18]
Stomach siRNA 27073556 [34]
Stomach siRNA 21805037 [35]
Liver siRNA 23419361 [36]
Liver siRNA 27323827 [37]
Liver siRNA 29928445 [38]
Pancreas siRNA 27738325 [39]
Pancreas siRNA Decreased Increased 27669292 [40]
Pancreas siRNA 22396793 [41]
Colon/Rectum siRNA 29439714 [42]
Colon/Rectum shRNA 29241219 [43]
Colon/Rectum shRNA 29037225 [15]
Colon/Rectum siRNA 26944315 [44]
Colon/Rectum siRNA 29512779 [45]
Ovarian siRNA 29848699 [46]
Prostate siRNA 26126522 [47]
Rhabdomyosarcoma shRNA 26496700 [48]
Lung cDNA 20219076 [52]
Liver cDNA 24482231 [49]
Liver cDNA 27359056 [50]
Liver cDNA Increased Decreased 29928445 [38]
Pancreas cDNA 27738325 [39]
Colon/Rectum cDNA 29037225 [15]
Colon/Rectum cDNA 29042987 [51]
Thyroid siRNA Decreased - 28804541 [54]
-: YAP gene silencing failed to promote cell apoptosis.

2.2. YAP Inhibits Apoptosis by Interacting with TEAD Transcription Factors

As a transcriptional co-activator, YAP does not contain a DNA-binding domain [4]. Thus, it requires
binding to transcription factors of the TEAD family, TEAD1-4 [56,57], to stimulate anti-apoptotic gene
expression (Figure 2). It has been demonstrated that YAP interacting with TEAD transcription
factors could increase the expression of anti-apoptotic genes, such as COX-2 [15], Survivin [16,17],
Int. J. Mol. Sci. 2018, 19, x 4 of 21
Int. J. Mol. Sci. 2018, 19, 3770 4 of 21
apoptotic gene expression (Figure 2). It has been demonstrated that YAP interacting with TEAD
transcription factors could increase the expression of anti-apoptotic genes, such as COX-2 [15],
and Glut1[16,17],
Survivin [18]. However,
and Glut1TEAD transcription
[18]. However, TEAD factors are not the
transcription soleare
factors transcription
not the solefactors, which
transcription
bind to YAP. It has been reported that p73 is also a transcriptional partner of YAP and
factors, which bind to YAP. It has been reported that p73 is also a transcriptional partner of YAP andpromotes the
expression
promotes the of expression
several pro-apoptotic genes such asgenes
of several pro-apoptotic p53AIP1
such [5], Bax [6,20],
as p53AIP1 [5],DR5 [7], and
Bax [6,20], DR5PUMA [8]
[7], and
(Figure 2). Thus, YAP can stimulate the expression of anti- as well as pro-apoptotic genes.
PUMA [8] (Figure 2). Thus, YAP can stimulate the expression of anti- as well as pro-apoptotic genes. This depends
on the
This transcriptional
depends partner of YAPpartner
on the transcriptional (Figureof2).YAP (Figure 2).

Figure 2.
Figure 2. The
The bivalent
bivalent role
role of
of YAP
YAP in
in apoptosis.
apoptosis. In
In the
the nucleus,
nucleus, yes-associated
yes-associated protein
protein (YAP)
(YAP) interacts
interacts
with TEA domain (TEAD) family transcription factors and initiates the expression of anti-apoptotic
with TEA domain (TEAD) family transcription factors and initiates the expression of anti-apoptotic
genes, such
genes, such asas Cyclooxygenase-2
Cyclooxygenase-2 (COX-2),
(COX-2), Survivin,
Survivin, and
and Glut1,
Glut1, to
to inhibit
inhibit apoptosis.
apoptosis. However,
However, nuclear
nuclear
YAP can
YAP can also
also interact with p73 to enhance the transcription of pro-apoptotic genes, such as p53AIP1,
p53AIP1,
Bax, DR5, and PUMA to promote apoptosis. T bar: Inhibition. Arrow: Increase.

2.3. YAP Inhibits

2.3. YAP Inhibits Apoptosis
Apoptosis by
by Increasing
Increasing Glycolysis
Glycolysis
Interestingly,
Interestingly, Wang
Wang et et al.
al. demonstrated
demonstrated thatthat glucose
glucose starvation can cause
starvation can cause YAP
YAP phosphorylation
phosphorylation
at serine 127 and inhibits YAP transcriptional activity in human embryonic
at serine 127 and inhibits YAP transcriptional activity in human embryonic kidney 293T (HEK kidney 293T (HEK
293T)
293T) cells and cervical cancer cells [19]. Consistent with these findings, Lin et al.
cells and cervical cancer cells [19]. Consistent with these findings, Lin et al. observed that knockdown observed that
knockdown of YAP significantly
of YAP significantly promoted cells promoted cells
apoptosis, apoptosis,
when when breast
breast cancer cancer
cells were cells were
cultured cultured
at high at
glucose
high glucose concentration [18]. However, when the cells were cultured at low glucose
concentration [18]. However, when the cells were cultured at low glucose concentration, the anti- concentration,
the anti-apoptotic
apoptotic role of YAProlewas
of YAP wasabolished
largely largely abolished [18]. In addition,
[18]. In addition, Wang
Wang et al. et al.
proved thatproved that YAP
YAP promotes
promotes the expression
the expression of Glut3,
of Glut3, which which isininvolved
is involved in glucose metabolism
glucose metabolism [19].suggest
[19]. These data These datathat suggest
glucose
that glucose starvation is an activator of Hippo-YAP signaling pathway, and that
starvation is an activator of Hippo-YAP signaling pathway, and that YAP inhibits apoptosis via YAP inhibits apoptosis
via regulating
regulating the the uptake
uptake of glucose.
of glucose.

2.4. YAP Inhibits

2.4. YAP Inhibits Apoptosis
Apoptosis via
via Enhancing
Enhancing the the Autophagic
Autophagic Flux
Flux
It
It has been reported that YAP decreases cisplatin-induced apoptosis
has been reported that YAP decreases cisplatin-induced apoptosis through
through activation
activation of
of
autophagy in ovarian cancer cells [58]. Moreover, Yan et al. reported that knockdown of
autophagy in ovarian cancer cells [58]. Moreover, Yan et al. reported that knockdown of YAP causes YAP causes
apoptosis via reducing
apoptosis via reducing mitophagy,
mitophagy, aa selective
selective degradation
degradation of of mitochondria
mitochondria by
by autophagy,
autophagy, in
in gastric
gastric
cancer cells [59]. In addition, Song et al. demonstrated that YAP enhanced the autophagic
cancer cells [59]. In addition, Song et al. demonstrated that YAP enhanced the autophagic flux flux to
to
reduce
reduce apoptosis
apoptosis inin nutrient
nutrient deprived
deprived breast
breast cancer
cancer cells
cells [60]. These publications
[60]. These publications are
are consistent
consistent with
with
Int. J. Mol. Sci. 2018, 19, 3770 5 of 21

the concept that YAP inhibits apoptosis via inducing autophagic flux. However, Liu et al. found that
inhibition of YAP accumulation failed to have an effect on apoptosis; but can induce autophagy in
thyroid papillary carcinoma cells [54]. This indicates that even though most publications support the
hypothesis that YAP inhibits apoptosis by increasing the autophagic flux, the YAP-induced autophagy
is not always the sole or most important factor to regulate apoptosis in cancer cells.

3. The Pro-Apoptotic Function of YAP

3.1. Clinical Evidence Suggests That YAP Is a Context Specific Tumor Suppressor
Several studies demonstrated that YAP promotes apoptosis in vitro and therefore can potentially
reduce tumor growth in vivo [5–8]. This implies that YAP can have an anti-oncogenic function. Indeed,
some clinical evidence supports the concept that YAP is a tumor suppressor in breast cancer and
hematological cancer [9,26]. Yuan et al. described that 63% of infiltrating ductal breast carcinomas had
lost YAP expression, but they did not demonstrate that the decreased YAP expression was associated
with a poor survival in breast cancer patients [26]. Cottini et al. found that low expression of YAP
was associated with short survival time in hematological cancer [9]. However, this conclusion was
based only on the analysis of YAP mRNA. Interestingly, this study also showed that upregulation of
YAP expression induces cell death in an ABL1 (Abelson murine leukemia viral oncogene homolog 1)
activity dependent manner [9]. Thus, these publications suggest that YAP can be a tumor suppressor
in a context specific manner.

3.2. YAP Promotes Apoptosis in a p73-Dependent Manner

It has been demonstrated that nuclear YAP interacts with p73, a tumor suppressor, to enhance
apoptosis in response to DNA-damage [6,61] (Figure 2). In addition, Levy et al. reported when normal
hematological cells suffer DNA damage stress, tyrosine kinase c-Abl (ABL1) enters the nucleus and
phosphorylates YAP on a tyrosine residue, Y357 [62]. The Y357-phosphorylated YAP binds to p73
to promote the transcription of pro-apoptotic genes, such as p53AIPI [5], Bax [6,20], DR5 [7], and
PUMA [8]. In addition, p300, which can activate p73, and promyelocytic leukemia (PML), which can
increase YAP stabilization, are also involved in regulating this effect of the YAP-p73 complex [6,61].
These publications demonstrate that YAP can promote apoptosis via interaction with the transription
factor p73.

4. A Multitude of Molecules Regulate Apoptosis and Hippo-YAP Signaling

Molecules, which inhibit or induce apoptosis and regulate Hippo-YAP signaling, were summarized
in Figure 3 and Table 2. In the nucleus, YAP often interacts with TEAD transcription factors to stimulate
the expression of anti-apoptotic genes [15,18,44]. However, it can also bind to p73 and promote the
expression of pro-apoptotic genes [5–8,20].

4.1. Activators of YAP, Which Impede Apoptosis

4.1.1. TFAP2C
The transcription factor AP-2 Gamma (TFAP2C) is a member of the activating protein 2 (AP-2)
family [63]. Some studies demonstrate that TFAP2C can increase the accumulation of cellular YAP in the
nucleus by inactivating MST1/2 [42,64]. Moreover, Wang et al. reported that overexpressed TFAP2C
could decrease the 5-fluorouracil-induced apoptosis in colorectal cancer cells [42]. Interestingly,
they observed that this effect of TFAP2C is dependent on Rho-associated protein kinase (ROCK).
This suggests that TRAFP2C inhibits apoptosis via YAP and ROCK signaling. Indeed, another
publication describes that the ROCK inhibitor, Y-27632, blocked the nuclear accumulation of YAP.
This demonstrates that ROCK signaling indeed regulates YAP [65]. These data imply that TFAP2C
inhibits cell apoptosis via ROCK-YAP signaling and suggest an anti-apoptotic function of YAP.
Int. J. Mol. Sci. 2018, 19, 3770 6 of 21
Int. J. Mol. Sci. 2018, 19, x 6 of 21

Figure Figure 3. Many

3. Many molecules
molecules regulateapoptosis
regulate apoptosisandand Hippo-YAP
Hippo-YAP signaling
signalingpathway.
pathway. Anti-apoptotic
Anti-apoptotic
molecules
molecules are are indicated in
indicated in blue,
blue,whereas
whereaspro-apoptotic molecules
pro-apoptotic are indicated
molecules arein indicated
green. Mostin anti-
green.
apoptotic molecules, such as metastasis associated lung adenocarcinoma transcript 1 (MALAT1),
Most anti-apoptotic molecules, such as metastasis associated lung adenocarcinoma transcript 1
serine/threonine kinase 38 like (STK38L), inhibitor of nuclear factor kappa B kinase subunit epsilon
(MALAT1), serine/threonine kinase 38 like (STK38L), inhibitor of nuclear factor kappa B kinase subunit
(IKBKE), Itch, S100 calcium-binding protein A1 (S100 A1), Ajuba, transcription factor AP-2 Gamma
epsilon (IKBKE), Itch, S100 calcium-binding protein A1 (S100 A1), Ajuba, transcription factor AP-2
(TFAP2C), WW domain binding protein 5 (WBP5), lncRNA PCGEM1, Ras homolog gene family,
Gamma (TFAP2C),
member WW domain
A (RhoA), binding
usually allow YAP protein 5 (WBP5),
to enter lncRNA
the nucleus PCGEM1,
to interact with Ras
TEAhomolog gene family,
domain (TEAD)
member A (RhoA), usually allow YAP to enter the nucleus to interact with TEA domain
family transcription factors and to activate the expression of anti-apoptotic genes. Some molecules, (TEAD) family
transcription factors
such as cAMP and toelement-binding
response activate the expression of anti-apoptotic
protein (CREB) and forkhead box genes. Some
protein A1molecules, such as
(FoxA1) inhibit
cAMPcell response
apoptosis element-binding protein (CREB)
by inducing the transcription of theand
YAPforkhead
gene. In box protein
addition, A1 (FoxA1)
deltaNp63 inhibit cell
can suppress
YAP by
apoptosis gene expression
inducing thetotranscription
impair p73-mediated
of the YAPapoptosis. However,
gene. In addition, thedeltaNp63
role of deltaNp63 in YAPYAP
can suppress genegene
expression
expression is stillp73-mediated
to impair a matter of controversy.
apoptosis. Moreover,
However, Calcium-binding
the role of deltaNp63 tyrosine phosphorylation-
in YAP gene expression
is stillregulated
a matter of protein (CABYR-a
controversy. and CABYR-b,
Moreover, CABYR-a/b)
Calcium-binding and phosphorylation-regulated
tyrosine phosphatidylinositide 3-kinase protein
(PI3K)/protein kinase B (AKT) signaling lead to phosphorylation of YAP at serine 127 and attenuate
(CABYR-a and CABYR-b, CABYR-a/b) and phosphatidylinositide 3-kinase (PI3K)/protein kinase B
nuclear YAP/p73-mediated apoptosis. Additionally, PI3K/AKT signaling can also suppress apoptosis
(AKT) signaling lead to phosphorylation of YAP at serine 127 and attenuate nuclear YAP/p73-mediated
by upregulate CD166 expression. Most of the pro-apoptotic molecules, such as G-protein-coupled
apoptosis. Additionally, PI3K/AKT signaling can also suppress apoptosis by upregulate CD166
receptors (GPCRs), cAMP-dependent protein kinase A (PKA), Crumbs-3 (CRB-3), Ras association
expression. Most of
domain family the pro-apoptotic
member molecules, such
6 (RASSF6), AMP-activation as kinase
protein G-protein-coupled
(AMPK), enhance receptors
apoptosis(GPCRs),
by
cAMP-dependent protein kinase
inducing phosphorylation A (PKA),
of YAP Crumbs-3
and thereby (CRB-3),
impairing Rasaccumulation
nuclear association domain
of YAP. In family member
addition,
6 (RASSF6), AMP-activation
some pro-apoptotic protein
molecules, kinase
such (AMPK),
as Fbxw7, enhancemiR132,
miR520c-3p, apoptosisandby inducing phosphorylation
hsa-miR-138-2-3p enhance
of YAP theand thereby impairing
degradation or block thenuclear accumulation
expression of YAP. In
of YAP. In addition, RASaddition, some
association pro-apoptotic
domain molecules,
family 1 isoform
such as A (RASSF1A) and early growth
Fbxw7, miR520c-3p, response-1
miR132, (EGR-1) can induce enhance
and hsa-miR-138-2-3p pro-apoptotic
the genes via the YAP-p73-
degradation or block the
p300-PML
expression complex.
of YAP. T bar: Inhibition.
In addition, Arrow: Increase.
RAS association domain family 1 isoform A (RASSF1A) and early
growth response-1 (EGR-1) can induce pro-apoptotic genes via the YAP-p73-p300-PML complex. T bar:
Inhibition. Arrow: Increase.
Int. J. Mol. Sci. 2018, 19, 3770 7 of 21

4.1.2. WBP5
Initially, WW domain binding protein 5 (WBP5) was described as a ligand that can bind to
FBP11 WW domain [66]. Recently, it was reported that WBP5 was involved in regulating the Hippo
pathway [67]. Tang et al. demonstrated that overexpressed WBP5 could inhibit the phosphorylation of
MST2 and YAP without changing the level of these two proteins in lung cancer cells [68]. Moreover,
immunofluorescence assays proved that upregulation of WBP5 induced the nuclear accumulation of
YAP and decreased apoptosis, whereas downregulation of WBP5 lead to YAP inactive and enhanced
cell apoptosis. These studies suggest an anti-apoptotic function of YAP and that WBP5 activates YAP
signaling and inhibits apoptosis.

4.1.3. lncRNA MALAT1 and STK38L

It has been reported that downregulation of lncRNA metastasis associated lung adenocarcinoma
transcript 1 (MALAT1) and serine/threonine kinase 38 like (STK38L) lead to the accumulation of LATS1
and decrease the level of cellular YAP in pancreatic cancer cells [69,70]. However, the mechanism,
how lncRNA MALAT1 and STK38L regulate the accumulation of LATS1 and YAP, is still unknown.
In addition, these studies also demonstrated that lncRNA MALAT1 and STK38L could inhibit apoptosis
via unknown mechanisms [69,70]. These anti-apoptotic effects may be mediated by YAP and suggest
an anti-apoptotic function of YAP.

4.1.4. IKBKE and Itch

Liu et al. demonstrated that the knockdown of nuclear factor kappa B kinase subunit epsilon
(IKBKE) dramatically elevated LATS1/2 concentration and serine 127-phosphorylated YAP in human
glioblastoma cells [71]. In contrast, it decreased the nuclear localization of YAP [71]. Moreover,
inhibition of IKBKE by amlexanox suppressed the accumulation of cellular YAP and the anti-apoptotic
protein, CYR61 [71,72]. These data imply that IKBKE may inhibit apoptosis by inducing the nuclear
localization of YAP. This suggests a pro-oncogenic activity of YAP [71].
In addition, it was reported that Itch, a HECT class E3 ubiquitin ligase, could complex with
LATS1 through the WW domains of Itch and the PPxY motifs of LATS1 [73]. Ho et al. reported that
downregulation of Itch not only provoked the stabilization of LATS1, but also induced phosphorylation
of YAP at serine 127 in HEK 293T cells [73]. In addition, downregulation of Itch induced cell death,
while overexpressed Itch yielded the opposite effect. Thus, these data suggest that Itch can inhibit the
phosphorylation of YAP and reduces apoptosis via enhancing LATS1 degradation. In addition, these
data suggest an anti-apoptotic activity of YAP.

4.1.5. S100 A1
Recently, Guo et al. demonstrated that S100 calcium-binding protein A1 (S100 A1), which interacts
with LATS1, inhibits the phosphorylation of this kinase and leads to decreased phosphorylation and
increased accumulation of cellular YAP [74]. The authors also demonstrated that knockdown of S100A1
by siRNA increased cisplatin-induced apoptosis. In addition, LATS1 depletion significantly reduced
the effects of S100A1 on apoptosis. Thus, this suggests that S100 A1 inhibits apoptosis and increases
the accumulation of YAP. This argues for an anti-apoptotic function of YAP.

4.1.6. Ajuba
It was reported that Ajuba, an actin binding and scaffolding protein, can interact with LATS1/2
and thereby inhibits the activation of this kinase [75]. This leads to decreased YAP phosphorylation [75].
Interestingly, Ajuba does not only decrease the phosphorylation of YAP, but also inhibits apoptosis
of cervical cancer cells [76]. This suggests that inhibition of apoptosis by Ajuba correlates with
decreased YAP phosphorylation and implies an anti-apoptotic function of YAP. However, we do not
fully understand if and how YAP signaling is important for the inhibition of apoptosis by Ajuba.
Int. J. Mol. Sci. 2018, 19, 3770 8 of 21

4.1.7. lncRNA PCGEM1 and RhoA

Prostate cancer gene expression marker 1 (PCGEM1) is an lncRNA that is initially found to be
overexpressed in aggressive prostate cancers [77]. Recently, Chen et al. reported that overexpressed
lncRNA PCGEM1 could decrease apoptosis in ovarian cancer cells [78]. Subsequently, they found
that upregulated lncRNA PCGEM1 increased the expression of RhoA, which can enhance activity
and accumulation of cellular YAP [79]. In addition, the authors also reported that downregulated
PCGEM1 could promote apoptosis via decreasing RhoA expression. However, silencing the expression
of RhoA reversed the anti-apoptotic effect of PCGEM1 and significantly inhibited the total level of
YAP protein [78]. This suggests that PCGEM1 inhibits apoptosis and induces the accumulation of YAP
via RhoA. Thus, YAP might have an anti-apoptotic function in this context.

4.1.8. CREB and FOXA1

Cyclic adenosine monophosphate (cAMP) response element-binding (CREB) protein is a
ubiquitous transcription factor that activates the transcriptional activity of various promoters [80].
Wang et al. reported that CREB could promote YAP transcription through binding to a novel region
(608/439 base pairs) within the YAP promoter in liver cancer cells [81]. In addition, the same research
group also found that CD166 could inhibit apoptosis via increasing the accumulation of CREB and
cellular YAP [49]. These studies suggest that YAP might be anti-apoptotic.
Some studies demonstrated that forkhead box protein A1 (FOXA1), a member of forkhead box
gene superfamily, inhibits apoptosis in cancer cells [82,83]. Consistent with these in vitro data, Ren et al.
observed that gastric cancer patients with high expression of FOXA1 had poorer five-year overall
survival [84]. Moreover, Ma et al. reported that FOXA1 could be detected in 57.8% (52/90) of the
colorectal cancer specimens, whereas only in 37.8% (34/90) of the non-cancerous specimens [85].
Moreover, the patients with FOXA1 expression had poor survival. It was also demonstrated that
FOXA1 knockdown evidently induced apoptosis; while it decreased the expression of YAP [85].
Interestingly, Yu et al. reported that in liver cancer cells FOXA1 was able to bind the R2 region of
the YAP promoter, which contains a CREB binding motif [86]. Additionally, FOXA1 overexpression
recruited CREB onto the R2 region. These data suggest that FOXA1 facilitates YAP transcription via
enhancing the binding of CREB to the YAP promoter. These studies demonstrate that FOXA1 inhibits
apoptosis and increases the expression of YAP, which suggests an anti-apoptotic function of YAP.

4.2. Activators of YAP, Which Induce Apoptosis

4.2.1. RASSF1A
Numerous studies have argued that RASSF1A (Ras association domain family 1 isoform A)
is a tumor suppressor [8,87,88]. Matallanas et al. found that RASSF1A allows YAP to move to
the nucleus and to interact with p73 [8]. The YAP-p73 complex results in transcription of the
pro-apoptotic target gene PUMA in breast cancer cells [8] and Ankyrin Repeat Domain 1 (ANKRD1),
which is in some circumstances considered to be a tumor suppressor gene, because it is epigenetically
inactivated in human cancer and reduces colony formation of cancer cells [87]. In addition, Yee et al.
found that a RASSF1A polymorphism, RASSF1A-p.133Ser, failed to enhance YAP-p73 mediated
apoptosis [88]. Furthermore, they demonstrated that male soft tissue sarcoma patients, who carried the
RASSF1A-p.133Ser allele, exhibited poorer tumor-specific survival [88]. This suggests that the tumor
suppressor function of RASSF1A may be due to YAP-p73 mediated apoptosis. However, Donninger
et al. reported that the anti-tumor function of RASSF1 is rather caused by inhibition of proliferation
than its pro-apoptotic effect [89]. Nevertheless, all these publications suggest that RASSF1A induces
apoptosis and that YAP can have a pro-apoptotic function, when interacting with p73.
Int. J. Mol. Sci. 2018, 19, 3770 9 of 21

4.2.2. EGR-1
Early growth response-1 (EGR-1) is a nuclear protein and functions as a transcriptional
regulator [90]. Zagurovskaya et al. demonstrated that EGR-1 interacts with YAP through its PPxY
motif and that this interaction is required for inducing clonogenic cell death in prostate carcinoma
cells [91]. In addition, several studies reported that EGR-1 served as a tumor suppressor in colorectal
carcinoma [92–94], gliomas [92–94], and colon carcinoma [92–94]. However, the role of EGR-1 in
cancer is still a matter of controversy [95]. For example, Virolle et al. proved that EGR1 promotes
the progression of prostate cancer [96]. These studies suggest that EGR-1 induces cell death and YAP
might have a pro-apoptotic function when interacting with EGR-1.

4.3. Inhibitors of YAP, Which Induce Apoptosis

4.3.1. GPCRs and PKA

G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, have been
considered to be upstream regulators of the Hippo pathway [14,97,98]. Yu et al. reported that
lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1-P) inhibit LATS1/2 activity via
blocking G12- and G13-coupled receptors, which activate YAP function and promote cell migration
and proliferation [14]. In contrast, GPCRs activators, such as glucagon and epinephrine could
activate LATS1/2 and inhibit YAP function [14]. Kim et al. observed that the GPRCs-triggered
LATS2-YAP pathway depends on cAMP-dependent protein kinase A (PKA) [97]. In addition, they
demonstrated that PKA could phosphorylate LATS2, and thereby enhances LATS2 activity sufficiently
to phosphorylate YAP at serine 381 [97], which leads to the degradation of YAP [99]. Moreover,
Zhang et al. also observed that GPCRs and PKA could induce YAP phosphorylation via promoting
LATS1 phosphorylation [98]. Consistent with these findings, the authors reported that induction of
apoptosis by omega-3 polyunsaturated fatty acid is mediated by GPCRs [98]. These data suggest
that GPCR/PKA signaling induces apoptosis and inhibits YAP function, suggesting an anti-apoptotic
function of YAP.

4.3.2. RASSF6
He et al. found that Ras association domain family member 6 (RASSF6) overexpression could
increase cisplatin-induced apoptosis, while depletion of RASSF6 had the opposite effect in breast cancer
cells [100]. The authors observed that RASSF6 decreased cellular YAP concentration and activated the
Hippo signaling pathway by upregulating the phosphorylation of MST1/2 and LATS1. In addition,
overexpression of YAP inhibited the RASSF6 and cisplatin-induced apoptosis. Thus, these data suggest
that RASSF6 induces apoptosis through activation of the Hippo pathway leading to the inhibition of
YAP function. These data suggest an anti-apoptotic function of YAP.

4.3.3. CRB-3
Recently, it was reported that crumbs-3 (CRB-3), the major crumbs isoform in mammalian
epithelial cells [101], is involved in Hippo signaling. Mao et al. found that overexpressed CRB-3
could induce the serine 127-phosphorylated YAP, and decreased the accumulation of nuclear YAP
protein in mammary epithelial cells [102]. In addition, they also reported in a xenograft study that
CRB-3 increased cell death within tumors. Moreover, Szymaniak et al. demonstrated that CRB-3
promoted the interaction between YAP and LATS1/2 in lung epithelial cells [103]. This led to increased
phosphorylation and cytoplasmic sequestration of YAP [103]. Thus, CRB-3 blocks YAP function and
induces cell death, implying a pro-oncogenic function of YAP.
Int. J. Mol. Sci. 2018, 19, 3770 10 of 21

4.3.4. AMPK
Mo et al. reported that the activation of AMP-activation protein kinase (AMPK) inhibits the activity
of YAP [104]. They demonstrated that metformin or aminoimidazole carboxamide ribonucleotide
(AICAR), two well-known AMPK activators, increased the serine 127-phosphorylated YAP in primary
mouse hepatocytes. Moreover, these two substances decreased the expression of anti-apoptotic
genes, such as CTGF and CYR61 [72,105]. Consistent with this study, Wang et al. also found that
an AMPKα1 C-terminal-truncated mutant (amino acids 1-312), which has been demonstrated to be
a constitutively active form of AMPK, induced the phosphorylation of YAP in HEK 293T cells [19].
In addition, Jiang et al. proved that resveratrol, a natural polyphenol present in most plants, inhibited
YAP accumulation in pancreatic cancer cells [40]. However, knockdown of AMPK rescued the
resveratrol-induced suppression of YAP [40]. This suggests that AMPK induces apoptosis and impairs
the function of YAP via enhancing YAP phosphorylation. This could lead in vivo to larger tumors,
suggesting a pro-oncogenic function of YAP.

4.3.5. Fbxw7, miR520c-3p, miR132, and hsa-miR-138-2-3p

It was suggested that F-box and WD repeat domain-containing 7 (Fbxw7), a well-known F-box
protein in the SCF (SKP1-CUL1-F-box protein) E3 ligase complex [106], can directly bind to YAP and
decreases the accumulation of YAP in hepatocellular carcinoma cells [107]. In addition, the proteasome
inhibitor MG132 was able to prevent the downregulation of YAP in Fbxw7 overexpressing cells,
suggesting that Fbxw7 targets YAP for degradation by proteasomes [107]. Tu et al. reported that
Fbxw7 expression could induce cell apoptosis and that restoring YAP expression lead to a significant
reduction of apoptosis [107]. Thus, these data suggest that Fbxw7 induces apoptosis by inducing
the degradation of YAP. Since loss of Fbxw7 expression was associated with poor clinicopathological
features including large tumor size [107], YAP might have a pro-oncogenic function in this context.
Some molecules, such as miR520c-3p [108] or miR132 [108], have been reported to enhance
the degradation of YAP and induce apoptosis of hepatocellular carcinoma cells by an unknown
mechanisms. In addition, Zhu et al. reported that hsa-miR-138-2-3p prevented the accumulation of
cellular YAP and induced apoptosis in human laryngeal cancer stem cells [109]. These publications
also argue for an anti-apoptotic function of YAP.

4.4. Inhibitors of YAP Which Impede Apoptosis

4.4.1. DeltaNp63
DeltaNp63 is an isoform of p63, which lacks the acidic transactivation (TA) domain and
antagonizes p53, TAp63 and TAp73 by inhibiting the expression of their downstream target genes [110].
Interestingly, Ehsanian et al. observed that deltaNp63 binds to the promotor of YAP and suppresses
YAP expression in head and neck cancer cells [111]. Surprisingly, Li et al. also observed that deltaNp63
directly binds to the YAP promoter, but claimed that this induces YAP gene expression in squamous
cell carcinoma cell lines [112]. Possibly, the effect of deltaNp63 on gene expression of target genes
depends on many additional transcription factors, which might be differently expressed in distinct cell
lines. In addition, Ehsanian et al. could also clearly demonstrate that deltaNp63 and the knock down
of YAP inhibits apoptosis [111]. This suggests that YAP has a pro-apoptotic effect in head and neck
cancer cells.

4.4.2. CABYR
Calcium-binding tyrosine phosphorylation-regulated (CABYR) protein is isolated from human
spermatozoa and participates in the sperm capacitation [113]. Recently, Xiao et al. described
that, in lung cancer cells, silencing of the CABYR-a and CABYR-b genes (CABYR-a/b) inhibits the
phosphorylation of YAP at serine 127, which usually leads to increased nuclear localization of YAP [7].
This study also demonstrated that silencing of CABYR-a/b increased the percentage of dead cells and
Int. J. Mol. Sci. 2018, 19, 3770 11 of 21

that this induction of apoptosis could be inhibited by knocking down of YAP and p73 [7]. Moreover,
overexpression of YAP plus p73, but not the expression of either protein alone, effectively promoted cell
apoptosis, suggesting that both proteins must be present to induce apoptosis. These data suggest that
depletion of CABYR-a/b sensitizes lung cancer cells to apoptosis in a YAP/p73 dependent manner [7].
This implies that YAP, when interacting with p73, has a pro-apoptotic effect in lung cancer cells.

4.4.3. PI3K/AKT
Current evidence demonstrates that activated phosphatidylinositide 3-kinase (PI3K)/protein
kinase B (AKT) signaling can phosphorylate YAP at serine 127 [114] (Table 2). The serine
127-phosphorylated YAP interacts with 14-3-3 and is sequestered in the cytoplasm, which attenuates
nuclear YAP/p73-mediated apoptosis [114]. Consistent with this publication, Ehsanian et al. could
also demonstrate that AKT can inhibit apoptosis via phosphorylating YAP at serine 127 [111].
In addition, PI3K/AKT signaling can also upregulate CD166 expression [49]. Subsequently, CD166
enhances YAP expression and activity to suppress apoptosis in liver cancer cells [49]. These data
suggest that PI3K/AKT signaling inhibits apoptosis by regulating YAP activity via at least two
different mechanisms.

Table 2. Molecules regulate Hippo-YAP signaling and apoptosis.

Molecule Target YAP Apoptosis PMID

a. Activators of YAP, which impede apoptosis
TFAP2C MST1/2 Increases nuclear YAP Decreased 29439714 [42]
WBP5 MST2 Increases nuclear YAP Decreased 27336605 [68]
lncRNA MALAT1 LATS1 Increases cellular YAP Decreased 29215734 [69]
STK38L LATS2 Increases cellular YAP Decreased 29108249 [70]
IKBKE LATS1/2 Decreases phosphorylation of YAP Decreased 29048430 [71]
Itch LATS1 Decreases phosphorylation of YAP Decreased 21383157 [73]
S100 A1 LATS1 Decreases phosphorylation of YAP Decreased 29901195 [74]
Ajuba LATS1/2 Decreases phosphorylation of YAP Decreased 20303269 [75]
lncRNA PCGEM1 RhoA Increases cellular YAP Decreased 29949791 [78]
CREB YAP Increases YAP gene transcription Decreased 24482231 [49]
b. Activators of YAP, which induce apoptosis
RASSF1A YAP Increases nuclear YAP Increased 17889669 [8]
EGR-1 YAP Forms a complex with YAP Increased 19137013 [91]
c. Inhibitors of YAP, which induce apoptosis
GPCRs PKA Phosphorylates YAP at serine 381 Increased 23644383 [97]
RASSF6 MST1/2 Decreases cellular YAP Increased 29964010 [100]
CRB-3 LATS1/2 Increases phosphorylation of YAP Increased 28079891 [102]
AMPK YAP Increases phosphorylation of YAP Increased 25751140 [104]
Fbxw7 YAP Increases YAP degradation Increased 24884509 [107]
miR520c-3p YAP Decreases YAP gene expression Increased 27633306 [108]
miR132 YAP Decreases YAP gene expression Increased 27633306 [108]
Hsa-miR-138-2-3p YAP Decreases cellular YAP Increased 28533948 [109]
d. Inhibitors of YAP, which impede apoptosis
deltaNp63 YAP Controversy in YAP gene expression Decreased 28923839 [111]
CABYR YAP Increases phosphorylation of YAP Decreased 26843620 [7]
PI3K/AKT YAP Increases phosphorylation of YAP Decreased 12535517 [114]
Phosphorylates YAP at serine 127.

5. Compounds, Regulating Hippo-YAP Signaling, Induce Apoptosis, and Impair Cancer

Some studies demonstrate that Hippo-YAP signaling might be a promising target for therapies
to impair cancer [115]. Since YAP is the most important functional component of the Hippo-YAP
signaling pathway, it may be a more promising therapeutic target than other proteins.
Several compounds have been proven to regulate apoptosis via, or partly via, regulating
Hippo-YAP signaling (Table 3). These compounds can be classified into five categories: (a) compounds
Int. J. Mol. Sci. 2018, 19, 3770 12 of 21

that regulate upstream molecules of YAP or YAP per se to inhibit YAP accumulation, such as omega-3
polyunsaturated fatty acids (ω-3 PUFAs) [98], gossypol [116], resveratrol [40], 17-DMAG [117],
amlexanox [71] and tubacin [117], norcantharidin [118,119], JQ1 [120], oligomeric proanthocyanidins
(OPCs) [121]; (b) compounds that promote the phosphorylation of YAP and block YAP nuclear
translocation, such as dobutamine [122], huaier [123], GCCSysm-4 (G4) [15], scutellarin [124] and
hydrogen sulfide-releasing oleanolic acid (HS-OA) [125]; (c) compounds that inhibit the interaction
of YAP and TEAD transcription factors, such as verteporfin [126–128] and CA3 [129], or inhibit the
interaction of YAP and p63, such as nicotine [130]; (d) compounds that increase YAP accumulation,
such as IBS003031 [131] and actinomycin D [132]; (e) compounds that regulate the YAP-p73 complex,
such as α-TEA [133]. Many of these mentioned compounds are currently used in clinical trials (Table 3).
This increases the expectation that targeting the Hippo-YAP signaling pathway will become an efficient
way to treat cancer.

Table 3. Compounds regulating Hippo-YAP signaling, tumor progression, and apoptosis.

Compounds Cancer Target TW/TV * Apoptosis Clinical Trials † PMID

Regulate upstream molecules of YAP or YAP per se to decrease YAP expression
ω-3 PUFAs CR GPCRs ? I >20 27506947 [98]
Gossypol Ovarian LATS1 ? I 10 25180175 [116]
Resveratrol Pancreas AMPK ? I 9 27669292 [40]
17-DMAG Breast HSP90 D I 4 28529458 [117]
Amlexanox Glioblastoma IKBKE D I 1 29048430 [71]
Tubacin Breast HDAC6 D I 0 28529458 [117]
29901163 [118]
Norcantharidin Lung YAP ? I 0
27903989 [119]
JQ1 Chondrosarcoma YAP ? I 0 28059436 [120]
OPCs CR YAP D I 0 29463813 [121]
Promote the phosphorylation of YAP and block YAP nuclear translocation
Dobutamine Stomach YAP ? I >20 25493021 [122]
Huaier Liver YAP ? I 6 29187885 [123]
G4 CR YAP D I 0 29037225 [15]
Scutellarin Breast YAP D I 0 29079722 [124]
HS-OA Liver YAP-14-3-3 D I 0 27437776 [125]
Inhibit the interaction of YAP and TEAD or the interaction of YAP and p63
Pancreas D I 28002618 [126]
Verteporfin UM YAP-TEAD ? I 9 28042502 [127]
CR ? I 27383277 [128]
CA3 Esophagus YAP-TEAD D I 0 29167315 [129]
Nicotine Esophagus YAP-p63 ? D >20 24621512 [130]
Increase YAP Expression
IBS003031 MM YAP ? I 0 29061667 [131]
Actinomycin
Liver YAP D I >20 27836738 [132]
D
Regulate the YAP-p73 complex
α-TEA Breast YAP-p73 ? I 1 21214929 [133]
* TW: Tumor weight; TV: Tumor volume; D: Decreased; † search in https://clinicaltrials.gov/; we excluded clinical
trial with status of not yet recruiting, suspended, terminated, withdrawn and unknown. ω-3 PUFAs: Omega-3
polyunsaturated fatty acids; CR: Colon/Rectum; GPCRs: G-protein-coupled receptors; LATS1: Large tumor
suppressor kinases1; AMPK: AMP-activation protein kinase; HSP90: Heat shock protein 9; IKBKE: Inhibitor of
nuclear factor kappa B kinase subunit epsilon; HDAC6: Histone deacetylase 6; OPCs: Oligomeric proanthocyanidins;
G4: GCCSysm-4; HS-OA: Hydrogen sulfide-releasing oleanolic acid; UM: Uveal melanoma; MM: Multiple myeloma.
?: Studies did not measure tumor weight or tumor volume.
Int. J. Mol. Sci. 2018, 19, 3770 13 of 21

6. Conclusions and Future Perspectives

In conclusion, current evidence suggests that YAP, the core component of Hippo-YAP signaling
pathway, has an ambivalent role in cell apoptosis. It can bind to TEAD transcription factors to promote
the transcription of anti-apoptotic genes, such as COX-2 [15], Survivin [16,17], and Glut1 [18]. However,
it can also initiate the transcription of pro-apoptotic genes, such as p53AIP1 [5], Bax [6,20], DR5 [7],
and PUMA [8]. In addition, the clinical data also demonstrate that YAP can function as an oncogene
in several cancers [21,22,27], while it can also serve as a tumor suppressor in breast cancer [60] and
hematological cancer [9]. This suggests YAP has ambivalent functions. It can promote or inhibit
tumor progression dependent on other signaling pathways and the cancer type. These data also imply
that a therapy, which targets the Hippo-YAP signaling pathway, might be of benefit to only a subset
of patients.
Thus, there are several questions that should be addressed before targeting Hippo-YAP signaling
pathway to treat cancer patients: One main question is, if YAP inhibitors in combination with traditional
drugs, such as gemcitabine and cisplatin, induce cell death and impair cancer growth. Several
promising studies have already demonstrated that YAP inhibitors can restore sensitivity to gemcitabine
and cisplatin in several cancers [40,134,135]. On the contrary, Gujral et al. described that nuclear YAP
enhances gemcitabine effectiveness by downregulating multidrug transporters [136]. In addition,
previous studies also found that YAP enhances p73 mediated apoptosis when DNA damage stress
is induced by cisplatin [5,6,62]. These contradictory studies suggest that YAP inhibitors might not
always inhibit tumor growth, but might also foster tumor growth. Other important questions are:
(a) Is nuclear YAP abnormally expressed in individual cancer types and is its expression associated
with poor survival or good survival of cancer patients? This is crucial for deciding, if a YAP inhibitor
or a YAP activator should be applied. (b) How do distinct drugs, which regulate Hippo-YAP signaling,
compare in their efficacy to each other? (c) Are some drugs especially useful, because they do not only
regulate YAP, but also modify other signaling pathways? These questions need to be addressed in
order to provide a solid basis for planning clinical trials.

7. Note
This review was performed according to the PRISMA guidelines. Publications were identified
by searching PubMed, on 5 July 2018, using the following search strategy: (Hippo [tiab] OR YAP
[tiab]) AND (apoptosis [tiab] OR autophagy [tiab]) AND (neoplasms [tiab] OR cancer [tiab]). Inclusion
criteria: We included all studies which investigated the “mechanism of interaction between YAP
and autophagy” or the “mechanisms of interaction between YAP and apoptosis”. Exclusion criteria:
We excluded article types, which were reviews or commentaries; literature written not in English and
irrelevant literature (literature which does not meet the inclusion criteria). We also added publications,
which were cited in the reference list of the included literature or suggested by reviewers. In addition,
we searched the ClinicalTrials.gov data base, in order to find clinical trials using drugs, which are
involved in regulating the Hippo-YAP signaling pathway.

Author Contributions: Conceptualization, X.Z., B.V., and D.Z.; Methodology, X.Z. and D.Z.; Literature Review,
X.Z. and A.A.; Writing—Original Draft Preparation, X.Z., D.Z., and B.V.; Writing—Review & Editing, X.Z., A.A.,
B.V., and D.Z.; Supervision, B.V. and D.Z.; Funding Acquisition, X.Z., B.V., and D.Z.
Funding: Xianbin Zhang was supported by the China Scholarship Council (grant number: 201608080159).
The study was supported by the Deutsche Forschungsgemeinschaft (DFG research group for 2591, grant number:
321137804, ZE 712/1-1 and VO312 450/15-1).
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Mol. Sci. 2018, 19, 3770 14 of 21

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