Involved related pathological processes
⑴ Relationship between YAP/TAZ and inflammation
An appropriate inflammatory response is critical for the restoration of
tissue homeostasis after injury or infection, but how this response is
regulated by the physical properties of the cellular and tissue
microenvironment is not fully understood [47].
Recently, multiple studies have revealed the role of YAP/TAZ in
regulating inflammatory and immune responses [74].
YAP/TAZ are primary sensors of the cellular microenvironment,
integrating cell polarity and mechanical signaling with growth factor
signaling and inflammation [4]. YAP/TAZ-dependent
function is associated with the termination of NF-κB-dependent
transcription of inflammatory genes by inducing IκBa expression[75]. Deletion of YAP/TAZ increases the expression
of inflammatory genes, resulting in elevated local inflammation and
enhanced accumulation and persistence of inflammatory cells[76]. Activation of the downstream molecules of
the Hippo pathway YAP/TAZ in hepatocytes can promote the expression of
inflammatory (TNF, IL1β) proteins, thereby stimulating hepatic
inflammation [77]. Additionally, increased nuclear
expression of YAP/TAZ, a mediator of the Hippo pathway in lung
epithelial type II cells, promotes AECII activity, whereas mice lacking
YAP/TAZ exhibit prolonged pulmonary inflammatory responses during
bacterial pneumonia and alveolar epithelial regeneration delay[76]. In the corneal epithelium, persistent
inflammation causes ECM deposition and fibrosis, leading to activation
of YAP/TAZ mechanotransduction [58]. In this
process, NF-κB is considered to be one of the important targets of
YAP/TAZ and plays an anti-inflammatory role in regulating innate
immunity and autoimmunity [76,78,79].
Phosphorylated YAP is sufficient to reduce inflammation in
osteoarthritis by inhibiting the NF-κB signaling pathway[78]. Overexpression of constitutively active TAZ
significantly reduces the secretion of inflammatory cytokines caused by
overactivation of the NF-κB pathway and Rictor siRNA transfection. The
Rictor/mTORC2 signaling pathway inhibits inflammation by inhibiting
YAP/TAZ degradation and YAP/TAZ nuclear translocation[74].
⑵ Relationship between YAP/TAZ and fibrosis
Recent studies have demonstrated aberrant activation of YAP/TAZ in
fibrosis in both animal models and human tissues[66]. YAP/TAZ is activated in response to
increased mechanical stress, such as when cells adopt a diffuse cell
morphology, undergo adhesion to a hard ECM, or deform due to substrate
topology. All of these conditions affect the structural organization of
the F-actin cytoskeleton, thereby favoring localized adhesion and actin
stress fiber formation [58]. In fibroblasts, ECM
stiffness mechanically activates YAP/TAZ, promoting the production of
profibrotic mediators and ECM proteins. This results in tissue
stiffness, which establishes a feedforward loop of fibroblast activation
and tissue fibrosis. In contrast, in epithelial cells, YAP/TAZ is
activated by disruption of cell polarity and increased ECM stiffness in
fibrotic tissue, thereby promoting epithelial cell proliferation and
survival [80].
⑶ YAP/TAZ and tissue, organ regeneration and wound
healing
YAP/TAZ has recently been shown to be a key mediator of wound healing
and tissue regeneration in response to tissue damage[1]. During these processes, YAP/TAZ is activated
by intracellular and external signals [2]. During
skin wound healing, YAP/TAZ-mediated nuclear signaling is indispensable
for TGF-β signaling [81]. Mechanistically,
calcitriol promotes crosstalk between the YAP/TAZ and TGF-β/Smad
signaling pathways, triggering EMT in keratinocytes during wound healing[82]. Extensive work has identified YAP/TAZ as key
regulators of cell proliferation and ’stemness’, especially during organ
growth and regeneration [83]. Exciting results
have been observed in mice stimulating organ repair and regeneration in
nonregenerative organs [84]. The mouse heart is
currently the most prominent example of the beneficial regenerative
effects of experimental activation of YAP/TAZ, but activation of YAP/TAZ
also contributes to the regeneration of other organs in adult mice,
including the liver [85], muscle, and gut[84,86]. These studies raise the possibility of
manipulating YAP/TAZ downstream of the Hippo pathway in injured human
organs as a means to stimulate regeneration of endogenous mechanisms.
However, therapeutic activation of YAP/TAZ for regeneration may have
significant risks, as its overactivation has been shown to promote
cancer development [84].
Role in gut-related diseases
⑴ The role of YAP/TAZ in inflammatory bowel disease
Crohn’s disease is a major form of inflammatory bowel disease
characterized by chronic inflammation, recurrent mucosal healing and
deposition of extracellular matrix (ECM) in the mucosa and submucosa,
leading to the development of structural fibrosis and intestinal
obstruction[87].
YAP/TAZ expression is significantly upregulated in stenotic fibroblasts,
which correlates with the YAP/TAZ target gene signature. Downregulation
of YAP/TAZ genes inhibits intestinal fibroblast activation. In
intestinal fibroblasts, YAP/TAZ is activated by the Rho-ROCK1 signaling
pathway. The high expression of YAP/TAZ is positively correlated with
the expression of ROCK1, which is a prognostic marker of intestinal
obstruction in CD patients [66]. Meanwhile, the
YAP/TAZ and TEAD1/2/4 genes are also transcriptionally regulated by the
Wnt/β-catenin signaling pathway in the intestine, and the nuclear
translocation of YAP/TAZ in tissue injury depends on the Src family
kinase signaling pathway. Therefore, when Src family kinases inhibit
LATS1/2, thereby driving YAP/TAZ to the nucleus, they activate
YAP/TAZ-TEAD-mediated transcription, thereby promoting intestinal tissue
regeneration [63]. The study also found that the
IL-6 coreceptor gp130 is activated during intestinal inflammation, and
the expression of a constitutively active form of gp130 is activated and
requires YAP/TAZ to induce enterocyte proliferative responses and
intestinal regeneration in a model of inflammatory colitis. Targeted
inhibition of YAP/TAZ in fibroblasts may be a potential therapeutic
strategy to inhibit intestinal fibrosis in CD[66].
⑵ The role of YAP/TAZ in intestinal cancer
YAP/TAZ are potent inducers of cell proliferation and, in many cases,
important drivers of tumorigenesis [4,19,88].
Activation or overexpression of YAP/TAZ has been shown to lead to
cellular transformation, tumor growth, metastasis and drug resistance[1,11]. Colorectal carcinogenesis typically begins
with constitutive WNT signaling, resulting in nuclear accumulation of
transcriptional coactivators, including YAP/TAZ. Thereafter, mutations
and epigenetic events follow, inducing genetic programs that drive
invasion and metastasis [89]. Consistently, TIAM1
was found to be part of a cytoplasmic destruction complex that regulates
TAZ/YAP stability. It was further found that, in naive intestinal
epithelial cells, when the destruction complex is inactivated, TIAM1 and
TAZ/YAP aggregate and translocate from the cytoplasm to the nucleus.
However, in the nucleus, TIAM1 continues to antagonize nuclear TAZ/YAP
function despite the formation of WNT signaling, thereby inhibiting cell
migration and invasion. In the cytoplasm, TIAM1 localizes to the
destruction complex and promotes TAZ degradation by enhancing its
interaction with bTrCP. Nuclear TIAM1 inhibits the interaction of
TAZ/YAP with TEADs and suppresses the expression of TAZ/YAP target genes
involved in epithelial-mesenchymal transition, cell migration and
invasion, thereby inhibiting the migration and invasion of colorectal
cancer cells [89]. The Hippo pathway in mammals
can also inhibit the phosphorylation of YAP/TAZ by the large tumor
suppressor (LATS) family of Hippo core kinases via interaction with
14-3-3 proteins and/or via the ubiquitin–proteasome pathway.
Degradation leads to cytoplasmic septum to inhibit intestinal tumor
development [15,90,91]. YAP and TAZ are downstream
molecules of the Hippo pathway and are widely expressed in human tissues
under normal physiological conditions. When the Hippo kinase module is
repressed, YAP and TAZ lose their phosphorylation and translocate to the
nucleus, inhibiting apoptosis and promoting EMT and tumor formation. YAP
can also suppress the activity of the Hippo pathway by activating the
PI3K/AKT pathway. The PI3K/AKT pathway is a critical transduction
pathway involved in regulating cell proliferation, and enhancement of
PI3K activity contributes to AKT activation and promotes the continued
growth of tumor cells[92]. On the other hand, the
transcriptional coactivators YAP/ TAZ act as key regulators of the
conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display
active chromatin profiles across diverse human tumors, highlighting a
pan-cancer epigenetic rewiring which at single-cell level distinguishes
malignant from normal cell populations. YAP/TAZ inhibition in
established tumor organoids causes extensive cell death unveiling their
essential role in tumor maintenance. The epigenetic landscape of human
CRC unveils the existence of an aberrant pan-cancer core of enhancers
regulated by the transcriptional coactivators YAP/TAZ and active in more
than 20 types of human malignancies[93].
Conclusion and prospects
YAP/TAZ acts as a homologous transcriptional coactivator and plays an
important role in promoting cell proliferation, stem cell maintenance,
and tissue homeostasis. In the inflammatory process, the deletion of
YAP/TAZ can increase the expression of inflammatory genes, leading to an
increase in local inflammation, the accumulation of inflammatory cells
and an increase in persistence. Simultaneous activation or
overexpression of YAP/TAZ has been shown to lead to cellular
transformation and tumor development. The persistent inflammatory
response, in turn, leads to abnormal activation of YAP/TAZ and promotes
local adhesion and the formation of actin stress fibers, which
subsequently leads to fibrosis. Overactivated YAP/TAZ can lead to cell
proliferation, metastasis, and EMT. Therefore, YAP/TAZ play an important
role in the process of intestinal disease. YAP/TAZ can regulate the
development of inflammation and the formation of fibrosis in the later
stages of intestinal inflammatory diseases. YAP/TAZ, which is
overactivated in intestinal tumor diseases, promotes cell
transformation, tumor growth, metastasis, and drug resistance. YAP/TAZ
is a multifunctional transcriptional activator that is a downstream
effector of the Hippo and Wnt pathways, plays a negative regulatory
role, participates in a variety of cellular responses and is closely
related to cell proliferation and metabolism. In addition, YAP/TAZ can
act upstream of Notch signaling by activating Notch receptors.
Therefore, this paper discusses the proteins related to YAP/TAZ binding,
the related pathways involved, the related pathological processes, and
their role in intestinal diseases. However, other relevant binding
proteins and mechanisms of action of YAP/TAZ in the course of intestinal
disease have yet to be discovered. We suspect that regulating the
expression of YAP/TAZ by regulating YAP/TAZ-related proteins and
pathways can improve the occurrence and development of intestinal
diseases. As people pay increasing attention to the role of YAP/TAZ in
disease, more regulatory mechanisms will be mined and make a major
achievement. Next step, we will study the clinical application of
YAP/TAZ in intestinal diseases and make the discovery of these
mechanisms benefit patients.