Review article 1

Two faces of Hippo: activate or suppress the Hippo pathway

in cancer
Jingwen Cao and Wenlong Huang

The Hippo pathway has generated considerable interest in strategy for cancer treatment. This review will provide a
recent years because of its involvement in several key summary of currently known compounds that activate or
hallmarks of cancer progression and metastasis. Research suppress the Hippo pathway. Anti-Cancer Drugs
on the Hippo signaling pathway in cancer has been used to 00:000–000 Copyright c 2017 Wolters Kluwer Health, Inc.
determine the activity of yes-associated protein (YAP) in All rights reserved.
tumorigenesis and disease progression. Previous studies Anti-Cancer Drugs 2017, 00:000–000
have shown that the Hippo pathway can be used as a target
to inhibit YAP activity and is a viable treatment for cancer. Keywords: Hippo pathway, tumor immune response, tumorigenesis

However, more studies are required to further advance our School of International Pharmaceutical Business, China Pharmaceutical
understanding of the Hippo signaling pathway in cancer. It University, Nanjing, China

has been shown that knockout of serine/threonine-kinases Correspondence to Wenlong Huang, PhD, China Pharmaceutical University,
LATS1/2 in the Hippo pathway suppresses cancer immunity #24 TongJiaXiang, Gulou District, Nanjing 210009, China
Tel: + 86 258 327 1487; fax: + 86 2583 271 512;
in mice. In addition, suppression of the oncogene YAP could e-mail: [email protected]
contribute toward cancer immune therapy. Therefore,
Received 26 June 2017 Revised form accepted 17 August 2017
regulation of Hippo signaling can be an attractive alternative

Introduction Central to the Hippo pathway is a protein kinase cascade.

Hippo signaling is an evolutionarily conserved pathway Once upstream activation signals are received, a complex
that controls organ size by regulating cell proliferation, formed by MST1/2 kinases and SAV1 phosphorylates and
apoptosis, and stem cell self-renewal [1]. Dysregulation activates LATS1/2, which in turn phosphorylate the tran-
of this signaling pathway contributes toward cancer scription co-activators YAP/TAZ [7]. Phosphorylation indu-
development [2]. In this review, we will provide a brief ces 14-3-3 binding and cytoplasmic retention of YAP [7].
introduction to the Hippo signaling pathway, with a focus This leads to spatial separation between YAP/TAZ and their
on components that are altered in human cancers. We nuclear target transcription factors [8]. In addition, YAP
will then focus on potential cancer therapies based on the phosphorylation also leads to β-transducin repeat-containing
Hippo pathway, and present issues and future directions E3 ubiquitin protein ligase-dependent degradation by pro-
for Hippo pathway-based anticancer strategies. teasomes [9,10]. However, once dephosphorylated, YAP/
TAZ translocate to the nucleus and interact with TEAD1-4,
as well as other transcription factors, to promote the
Components of the Hippo pathway expression of genes that contribute toward cell proliferation
The Hippo signaling pathway, also known as the and survival [11] (Fig. 1).
Salvador/Warts/Hippo pathway, has emerged recently as
a growth control pathway. It was first discovered in
Drosophila melanogaster, and was later shown to be highly Role of the Hippo pathway in cancer
conserved in humans [3,4]. The Hippo pathway consists Deregulation of the Hippo pathway in cancer
of a core serine–threonine kinase cascade and a tran- There is considerable evidence to suggest that the Hippo
scriptional module. The kinase cascade includes mam- pathway is frequently deregulated in a broad range of
malian STE-20-like protein kinases 1/2 (MST1/2) and human cancers, including breast, ovarian, colorectal, lung,
large tumor-suppressor kinases 1/2 (LATS1/2) [5]. The and liver cancers; this is often correlated with poor
transcriptional co-factors, yes-associated protein (YAP), patient prognosis [12–14].
and transcriptional co-activator with PDZ-binding motif
(TAZ) together form the transcriptional module [6]. YAP primarily resides in the cytoplasm in normal human
Upon entering the nucleus, YAP/TAZ bind to the tran- tissues. Immunohistochemical staining of tumor tissues
scription factor TEAD and upregulate genes important indicated that deregulation of the Hippo pathway results
for proliferation and cell survival. It has been shown that in prolonged nuclear localization of YAP. Binding of YAP
YAP and TAZ are the main proteins that modulate sig- to TEAD initiates growth and survival-associated tran-
naling in the Hippo pathway [6]. scriptional programs.
0959-4973 Copyright
c 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/CAD.0000000000000559

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 2 Anti-Cancer Drugs 2017, Vol 00 No 00

Fig. 1 ubiquitin ligase CRL4 (DCAF1). This consequently

inhibits ubiquitination of LATS1/2 and inactivates YAP.
It is still unclear why mutations in Hippo signaling
pathway genes are so rare as YAP and TAZ activation is
observed in a broad range of human cancers. It is possible
that cross-networks such as Wnt [34], transforming
growth factor-β–bone morphogenetic protein (TGF-
β–BMP) [35], Notch [36], epithelial growth factor
receptor (EGFR) [37], and G-protein-coupled receptor
(GPCR) [38] frequently harbor oncogenic mutations,
which affect YAP/TAZ activation. Activation of these
pathways has been correlated with immunohistochemical
detection of nuclear YAP and TAZ in tumor tissues
[39–43]. Further investigation is required to define the
major oncogenic sources that cause YAP and TAZ acti-
vation in various tumor types.
Epigenetic alteration may be another mechanism by
which YAP and TAZ are activated in some human
tumors. Approximately 50% of breast cancers and
60–70% of astrocytomas have been shown to have
hypermethylated LATS1/2 promoter regions that limit
the expression of these genes [23,24]. In 37% of soft
tissue sarcomas and 20% of sarcomas, the MST1/2 pro-
Core of the Hippo pathway. moter regions were also shown to be hypermethylated
[44]. In addition, YAP amplification was observed on
chromosome 11q22 amplicons [16]. These results sug-
gested that downregulation of Hippo signaling by epi-
Elevated levels and nuclear localization of YAP have
genetic silencing of key activators and amplification of
been reported in a majority of solid cancers; these factors
YAP is associated with various lethal cancers.
are also strongly associated with adverse overall survival
and disease-free survival time in numerous cancers,
Hippo pathway as a suppressor signal for
suggesting that YAP1 may act as a potential therapeutic
tumorigenesis
target for these malignancies [12,14–20].
YAP/TAZ are pervasively activated in many human
tumors [12,45,46]. Elevated YAP and TAZ activity was
Potential mechanisms of Hippo pathway deregulation shown to induce tumors in several mouse models. In a
in cancer YAP transgenic model, overexpression of YAP con-
Approximately 50% of human liver cancers result in tributes toward the development of hepatocellular carci-
elevated YAP levels [21] and TAZ overexpression is noma [47], promotes irregular expansion in liver tissues,
observed in over 80% of breast cancers [19,22]. These and is associated with undifferentiated intestinal pro-
findings suggest that amplification of YAP and TAZ is a genitor cells [15]. Furthermore, YAP overexpression in
common mechanism underlying some human cancers. the KRASG12D lung cancer mouse model accelerated lung
However, alternative mechanisms predominate in other adenocarcinomas progression [48]. YAP overexpression
types of cancers, and could include mutation of Hippo also contributes toward radiation resistance by induction
pathway genes, promoter methylation, epigenetic silen- of genomic instability [49]. Therefore, YAP activation
cing of MST and LATS kinases [23–25], and expression confers potent cell proliferative capacity and resistance to
and/or upregulation of proteins that control Yap tran- apoptosis, which can eventually lead to cancer develop-
scription [26–29] and stability [28]. ment [46]. In addition, TAZ-induced transcriptional
activation of ZEB1/2 stimulates epithelial-to-mesenchy-
Recent reports on the basis of data from The Cancer
mal transition [50,51].
Genome Atlas and Catalogue of Somatic Mutation in
Cancer census suggested that Hippo pathway genes, with Mouse models with deletions in MST1/2, SAV1, MOB1A/
the exception of NF2 and TAZ, are not cancer-related B, and LATS1/2 all show upregulated expression of
genes [12]. NF2 encodes the tumor-suppressor protein TEAD target genes, increased expansion of progenitor
merlin, which regulates the Hippo pathway by promoting cells, as well as tissue overgrowth or tumorigenesis.
localization of LATS kinases to the plasma membrane Combined MST1/2 deficiency in the liver results in loss
[30–32]. Li et al. [33] found that merlin could bind to of inhibitory Ser127 phosphorylation on YAP1, massive
DCAF1 in the nucleus to suppress the activity of the E3 cell overgrowth, and hepatocellular carcinoma [52–54].

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 Two faces of Hippo Cao and Huang 3

In addition, studies have shown that in liver-specific YAP and TAZ through TEAD-mediated transcription is
LATS1/2-knockout and MOB1-deficient mice, the liver is required for in-vivo tumor growth suppression by
filled with highly proliferated immature biliary epithelial LATS1/2 deletion. This study uncovered a key role of the
cells [39,55]. Moreover, the deletion of SAV1 in hepato- Hippo pathway in modulating tumor immunogenicity,
cytes and intestinal epithelial cells leads to an increase in and showed that activation of the Hippo pathway may be
hepatic and intestinal progenitor cells, respectively [56,57]. a potential form of tumor therapy.
In the hypomorphic MOB1 mouse model, various types of
Activating the Hippo pathway may promote antitumor
tumors are developed [58]. Dysregulation of the Hippo
immune response, and therefore, would be an attractive
signaling pathway and increased YAP/TAZ activity induce
approach for cancer treatment. Furthermore, LATS1/2
expansion of tissue-specific stem/progenitor cells that
inhibition may enhance the efficacy of immune check-
eventually leads to cancer development. Therefore, clar-
point inhibitors. Thus, a combination of Hippo pathway
ification of the potential roles of the Hippo signaling
activators and immune checkpoint inhibitors could be a
pathway in tissue homeostasis and cancer stem cells can aid
novel therapeutic approach for immunogenic cancers,
in the advancement of cancer therapy.
especially in cases where malignancy is driven by onco-
genic alterations that do not affect the Hippo signaling
Hippo pathways have different tissue-specific and cell-
pathway. As germline or somatic mutations that affect the
type-specific physiological roles
core components of the Hippo pathway are uncommon in
It is generally accepted that the Hippo pathway is a
human cancers, it is expected that activation of the Hippo
tumor suppressor that inhibits the proliferation and sur-
pathway can enhance tumor immunity in most cancer
vival of normal cells, thus preventing tumorigenesis
types (Fig. 2).
[10,12,59]. However, a few studies have suggested that
the Hippo pathway can also exert oncogenic effects
under certain contexts [60,61]. Therapeutic targets in the Hippo pathway: reactivation of
the Hippo pathway
The correlation between Hippo signaling and cancer is Targeting kinases
tissue and cell specific. For example, the epidermis of Generally, kinases are the best targets for small molecule
mice with a skin-specific deletion of MST1/2 or LATS1/2 therapeutics. Unlike most of the oncogenic kinase targets
showed normal morphology, and YAP-S127 phosphor- used in current cancer therapies, the majority of kinases
ylation was not increased [62]. In addition, no kidney in the Hippo pathway are tumor suppressors. Restoring
defects or YAP activation were observed following the the function of tumor-suppressor kinases is indeed a
deletion of MST1/2 or SAV1 [63]. These studies indicated challenging task; activation of MST or LATS kinases for
that YAP activity is not always elevated during restriction anticancer therapy is even more challenging as there are
of core Hippo components. Similarly, it has been shown few options for the rational design of small molecule
that the oncogenic phenotype does not always occur with agonists [65].
YAP activation. It was observed that intestinal epithelial
cell-specific YAP expression leads to rapid loss of Targeting F-actin
intestinal crypts and inhibition of Wnt-mediated intest- F-actin modulates YAP/TAZ nuclear translocation,
inal regeneration [60]. These results suggested that the allowing cells to upregulate proliferation and survival
Hippo signaling pathway and YAP/TAZ exert different genes [66–68]. Therefore, it is reasonable to speculate
tissue-specific or cell-type-specific effects. that drugs that target F-actin may be effective in control
of tumor growth. The F-actin destabilizers, cytochalasin
The Hippo pathway kinases LATS1/2 suppress cancer D, the RHO kinase inhibitor Y27632, and the nonmuscle
immunity myosin II inhibitor blebbistatin all promote nuclear
For decades, most research groups have focused on the export of YAP and TAZ [69–72]. However, the impor-
suppressor role of the Hippo pathway in cancer. tance of the actin cytoskeleton for various basic cellular
However, the role of the Hippo pathway in the context of functions places limits on their usage. Therefore, appro-
reciprocal interactions between tumor cells and host priate doses of F-actin inhibitors need to be chosen to not
antitumor immune responses remains largely unknown. only show therapeutic efficacy but also to produce
Moroishi et al. [64] reported that loss of the Hippo minimal side effects.
pathway kinases LATS1/2 promotes tumor cell growth
in vitro, but inhibits tumor growth in murine syngeneic Targeting the GPCR signaling pathway
tumor models. Furthermore, adaptive immune responses GPCRs are the largest and most diverse group of mem-
induced by LATS1/2 deletion cause tumor regression. brane receptors in eukaryotes. These cell surface recep-
Mechanistically, it has been shown that nucleic acid-rich tors function like an inbox for messages in the form of
extracellular vesicles secreted by LATS1/2-null tumor light energy, peptides, lipids, sugars, and proteins.
cells induce type I interferon responses by the Toll-like Yu et al. [73] reported that YAP/TAZ is regulated robustly
receptor-MYD88/TRIF pathway. Hyperactivation of by many GPCRs and their cognate ligands, and

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 4 Anti-Cancer Drugs 2017, Vol 00 No 00

Fig. 2

Role of the Hippo pathway in cancer.

established the general function of GPCRs in YAP/TAZ enhancer element within the first intron of the YAP gene
regulation. GPCRs usually activate downstream signaling to drive YAP expression. In addition, detachment of β-
through heterotrimeric G proteins. Gα12/13-coupled, catenin from the destruction complex formed by APC,
Gαq/11-coupled, and Gαi/o-coupled signals induce YAP/ AXIN, and GSK3 resulted in inhibition of YAP/TAZ
TAZ activity, whereas Gαs-coupled signals repress YAP/ degradation [74]. Therefore, targeting the Wnt pathway
TAZ activity. Stimulation of Gs-coupled receptors by would be an effective option for inhibition of YAP/TAZ
glucagon or epinephrine activates LATS1/2 kinase transcription. Tankyrase inhibitors such as G244-LM,
activity, thereby inhibiting YAP function. Therefore, G007-LK, and XAV939 could increase AXIN activity and
development of small-molecule agonists targeting Gαs restore the integrity of the β-catenin destruction com-
may be an effective therapeutic option. plex, leading to YAP/TAZ degradation [75–77].

Targeting the Wnt/β-catenin signaling pathway YAP and TEAD as therapeutic targets
Konsavage et al. [29] implicated YAP as an oncogene Functionally, the most attractive therapeutic targets in
whose expression is driven by aberrant Wnt/β-catenin the Hippo pathway are the key oncoproteins, YAP and
signaling in human CRC cells. Once Wnt signaling is TAZ. YAP and TAZ are the final common conduits of
turned on, β-catenin/TCF4 complexes bind to a DNA the Hippo signaling pathway, and transmit signals from

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 Two faces of Hippo Cao and Huang 5

the core kinase cassette and upstream regulatory proteins upregulate YAP and TAZ function, which may prove
to a progrowth transcriptional program. beneficial in activation of the Hippo pathway.

Verteporfin Targeting MST1

Liu-Chittenden et al. [78] screened a small-molecule Anand et al. [84] reported the development of a potent
FDA-approved drug library for targeting the integrity of and selective MST1 kinase inhibitor based on a ruthe-
the TEAD–YAP transcription factor complex. Three nium half-sandwich scaffold. This compound was shown
compounds (protoporphyrin IX, hematoporphyrin, and to inhibit MST activity in vitro and in cultured Hela cells,
verteporfin) stood out among the top hits, all of which as measured by Histone H2B phosphorylation in
belong to the porphyrin family. Verteporfin, a benzo- response to apoptosis. However, its effects on YAP/TAZ
porphyrin derivative, is in clinical use as a photosensitizer activity have not yet been reported. The 9E1 antibody
in photocoagulation therapy for macular degeneration shows significant, although not complete, selectivity for
[79]. More importantly, verteporfin was moderately MST1 over other kinases, and provides a starting point
effective in blocking mouse hepatic tumorigenesis driven for the development of more selective MST1 inhibitors.
by Yap1 overexpression or loss of Nf2 [78], suggesting MST1 and MST2 (MST1/2) kinases, the mammalian
that it functions downstream of both of these alterations. Hippo orthologs, are central components of the Hippo
This strategy may be particularly appealing for tumors signaling pathway, and are therefore ideal target candi-
that are linked to mutations in Nf2, such as brain and dates for pharmacological induction of the Hippo pathway
neural tumors. [85]. Fan and colleagues reported the discovery of a
reversible and selective MST1/2 inhibitor, XMU-MP-1,
VGLL4-mimicking peptide using an enzyme-linked immunosorbent assay-based high-
VGLL4 directly competes with YAP in binding to throughput biochemical assay. XMU-MP-1 showed
TEADs, and serves its growth-inhibitory function excellent in-vivo pharmacokinetics, and could promote
through two TDU domains [80,81]. On the basis of the mouse intestinal repair. In addition, an intraperitoneal
structure of the VGLL4–TEAD4 complex, Jiao et al. [82] injection of XMU-MP-1 stimulated liver repair and
developed a peptide-based YAP inhibitor that mimics the regeneration in both acute and chronic liver injury mouse
function of VGLL4. This peptide could suppress tumor models at a dose of 1–3 mg/kg. The next step is to utilize
growth of human primary gastric cancer in nude mice and XMU-MP-1 for tumor therapies. We predict that future
inhibit tumorigenesis in the Helicobacter pylori-infected tumor therapies that use Hippo pathway activators will be
mouse model of gastric cancer [82]. heavily dependent on immune responses.

Flufenamic acid Targeting GPCR

Pobbati et al. [83] reported the discovery of a central GPCRs usually activate downstream signaling through
pocket in the YAP-binding domain (YBD) of TEAD. heterotrimeric G proteins. Yu et al. [73] showed that sti-
Screening of compounds that target this central pocket in mulation of Gα12/13-coupled, Gαq/11-coupled, and Gαi/
YBD was performed by differential scanning fluorimetry. o-coupled signals with lysophosphatidic acid (LPA),
X-ray crystallography studies showed that flufenamic sphingosine 1-phosphophate, and thrombin induced
acid, a NSAID, binds to the central pocket of TEAD2 YAP/TAZ activity. Serum-borne LPA and sphingosine
YBD. Biochemical and functional analyses further 1-phosphophate act through G12/13-coupled receptors to
showed that binding of NSAIDs to TEAD inhibits inhibit the Hippo pathway kinases, LATS1/2. This
TEAD–YAP-dependent transcription, cell migration, and results in the activation of the transcription co-activators,
proliferation, indicating that the central pocket is YAP and TAZ, which are oncoproteins repressed by
important for TEAD function. These studies pointed to a LATS1/2. YAP and TAZ are involved in LPA-induced
novel approach to targeting TEAD transcription factors, gene expression, cell migration, and proliferation [86].
and set the stage for therapeutic development of specific
TEAD–YAP inhibitors against human cancers. Discussion
High YAP and TAZ activity has been shown in various
Therapeutic targets in the Hippo pathway: suppression types of cancer. However, genetic mutations in the
of the Hippo pathway Hippo core components, YAP and TAZ, are rare [87].
Targeting kinase This implies that aberrant activation of the Hippo path-
Decades of targeted drug development efforts suggest way may be insufficient for tumorigenesis in vivo.
that kinases and enzymes are the most attractive targets
for small-molecule therapies. MST1/2 and LATS1/2 are Combination therapy
two pairs of kinases at the core of the Hippo signaling Activation of YAP may be triggered by other biological
pathway, and act to restrain YAP and TAZ activity. Small- processes that are sensitive to oncogenic mutations.
molecule inhibitors of these kinases are predicted to Understanding the synergistic effects between the Hippo

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 6 Anti-Cancer Drugs 2017, Vol 00 No 00

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