Next Article in Journal
State of the Art on CAR T-Cell Therapies for Onco-Haematological Disorders and Other Conditions
Previous Article in Journal
Impact of Physical Exercise on Quality of Life, Self-Esteem, and Depression in Breast Cancer Survivors: A Pilot Study
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Onco
Volume 4
Issue 3
10.3390/onco4030016
onco-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Targeting the Hippo- Yes-Associated Protein/Transcriptional Coactivator with PDZ-Binding Motif Signaling Pathway in Primary Liver Cancer Therapy

by
Yina Wang
1,* and
Liangyou Rui
1,2
1
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
2
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
*
Author to whom correspondence should be addressed.
Onco 2024, 4(3), 217-231; https://doi.org/10.3390/onco4030016
Submission received: 18 July 2024 / Revised: 13 August 2024 / Accepted: 20 August 2024 / Published: 22 August 2024
Browse Figure
Review Reports Versions Notes

Abstract

:

Simple Summary

The Hippo signaling pathway, an evolutionarily conserved cascade, plays a crucial role in regulating organ size, tissue regeneration, and tumorigenesis. The dysregulation of this pathway leads to the activation and nuclear translocation of YAP/TAZ, the pivotal downstream regulators. The Hippo-YAP/TAZ pathway promotes cell proliferation and tumorigenesis, notably in primary liver cancer. The Hippo-YAP/TAZ cascade has emerged as a significant therapeutic target in liver cancer. This review provides a comprehensive summary of recent advances in the Hippo-YAP/TAZ signaling pathway in primary liver cancer, highlighting its therapeutic potential as a target for intervention.

Abstract

Liver cancer imposes a pervasive global health challenge, ranking among the most prevalent cancers worldwide. Its prevalence and mortality rates are on a concerning upward trajectory and exacerbated by the dearth of efficacious treatment options. The Hippo signaling pathway, originally discovered in Drosophila, comprises the following four core components: MST1/2, WW45, MOB1A/B, and LATS1/2. This pathway regulates the cellular localization of the transcriptional coactivator Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) through a series of enzymatic reactions. The Hippo-YAP/TAZ pathway maintains a balance between cell proliferation and apoptosis, regulates tissue and organ sizes, and stabilizes the internal environment. Abnormalities of any genes within the Hippo signaling pathway, such as deletion or mutation, disturb the delicate balance between cell proliferation and apoptosis, creating a favorable condition for tumor initiation and progression. Mutations or epigenetic alterations in the Hippo signaling pathway components can lead to its inactivation. Consequently, YAP/TAZ becomes overexpressed and activated, promoting excessive cell proliferation and inhibiting apoptosis. This dysregulation is closely associated with the development of liver cancer. This review discusses the pivotal role of the Hippo signaling pathway in the pathogenesis and progression of liver cancer. By elucidating its mechanisms, we aim to offer new insights into potential therapeutic targets for effectively combating liver cancer.

1. Introduction

Global liver cancer incidence is increasing rapidly, and liver cancer is one of the leading causes of cancer-related death worldwide, with a 5-year survival rate as low as 30–40% [1,2]. Primary liver cancer is a prevalent clinical malignancy encompassing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). In 2020, primary liver cancer had a global incidence of 4.7% and a mortality rate of 8.3%, ranking fifth among common malignancies and third among cancer-related causes of death worldwide [3]. Liver cancer is often diagnosed at advanced stages due to difficulties in early diagnosis, high metastatic potential, and frequent recurrence, resulting in a poor prognosis with a low 5-year survival rate [4]. Therefore, understanding the pathogenesis of and influencing factors for primary liver cancer, as well as exploring new therapeutic targets, are currently challenging and have become a focal point in research. The Hippo-YAP/TAZ signaling pathway is well-established in regulating cell proliferation, embryonic development, tissue and organ sizes, liver development, and liver regeneration [5,6]. As research progresses, its role in tumor development has emerged, particularly in regulating liver cancer cell proliferation, metastasis, and the tumor microenvironment (TME) [7]. This review summarizes mechanisms by which the Hippo- Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) pathway regulates primary liver cancer development and discusses the advances in targeting this pathway to hinder cancer progression. We aim to explore novel effective therapies for primary liver cancer.
The Hippo signaling pathway primarily consists of upstream core kinases and downstream transcriptional coactivators. In mammals, the upstream kinases include Ste20-like kinases 1/2 (MST1/2) and large tumor suppressor 1/2 (LATS1/2). Downstream transcriptional coactivators primarily comprise YAP and TAZ [8]. MST1/2 phosphorylate and activate LATS1/2, and LATS1/2 in turn phosphorylate and inhibit YAP/TAZ activity. 14-3-3 protein binds to phosphorylated YAP/TAZ and retains YAP/TAZ in the cytoplasm; additionally, phosphorylation promotes the ubiquitination and degradation of YAP/TAZ [7,8]. When cells detect signals such as cell-to-cell contact, cell polarity, energy levels, and stress, the MST1/2 and LATS1/2 kinase cascade is activated to suppress YAP/TAZ. In contrast, inhibition of the Hippo signaling pathway suppresses YAP/TAZ phosphorylation, and non-phosphorylated YAP/TAZ enter the nucleus and bind to TEA domain 1/ (TEAD1/4), stimulating the transcription of target genes. This process promotes cell proliferation, suppresses apoptosis, and regulates tissue growth [9]. The mutation or deletion of genes associated with the Hippo signaling pathway is linked to apoptosis suppression, uncontrolled cell proliferation, and accelerated tumor progression, thus impacting patient prognosis [10,11]. The Hippo signaling pathway has been established to play a crucial role in tumorigenesis across various organs, including the liver. YAP/TAZ transcriptional co-factors are a pivotal downstream effector of the Hippo pathway to govern migration, proliferation, and survival. The aberrant activation of YAP is critical for the proliferation of both HCC and iCCA cells [12]. The Hippo-YAP/TAZ signaling pathway has emerged as a promising new target for clinical prevention and treatment of cancer. This article provides a comprehensive review of the Hippo-YAP/TAZ pathway in the initiation and progression of liver cancer.

2. Hippo/YAP Signaling Pathway

The Hippo/YAP signaling pathway, originally discovered in Drosophila, comprises a cascade of protein kinases (MST1/2, LATS1/2) and transcriptional regulators (YAP, TAZ, TEAD) [13]. Since the beginning of the 21st century, scientists have conducted extensive research on the Hippo signaling pathway and uncovered numerous related genes. It became evident that this pathway constitutes a protein kinase cascade and transcriptional coactivators and pivotally regulates liver tissue homeostasis [14,15]. Active YAP/TAZ, which are central to the pathway, undergo nuclear translocation and then activate the transcription of target genes [16]. YAP/TAZ’s target genes regulate development, cell proliferation, migration, survival, and other critical functions. YAP/TAZ is upregulated in solid tumors and exhibits oncogenic characteristics [17,18]. Hayashi et al. discovered that the expression of both TAZ and YAP is elevated in liver cancer [19]. Wu et al. observed that in patients with liver cancer, high YAP expression is associated with large tumors, multiple foci, liver cirrhosis, vascular infiltration, and intrahepatic metastasis [20].
Under physiological conditions, the Hippo signaling pathway maintains a dynamic balance between cell proliferation and apoptosis. This balance regulates the development and maturation of tissues and organs, suppresses tumorigenesis, and ensures the stability of the internal environment [21]. The primary function of the Hippo signaling pathway (i.e., MST1/2, LTAS1/2) is to deactivate key effector molecules (YAP/TAZ), thereby rendering the transcription co-factors inactive. This action blocks the expression of genes, such as cyclin E, cyclin D1, β-catenin, AXL receptor tyrosine kinase (AXL), cysteine-rich 61 (CYR61), and connective tissue growth factor (CTGF), which are involved in cell proliferation, adhesion, migration, and invasion [22,23].
In the Hippo signaling pathway, YAP is subjected to negative regulation through a phosphorylation cascade of MST1/2 and LATS1/2 [24]. The kinase activity of MST1/2 can be activated through binding to Salvador family WW domain-containing protein 1 (WWC1), a scaffold protein that also forms complexes with LATS1/2. MST1 also interacts with the members of the Ras association domain family, further enhancing kinase activity [25,26]. MST1/2 activates LATS1/2 by phosphorylating LATS1/2, as well as Mps-one binder kinase activator-like 1 (MOB1), a LATS1/2-binding protein [27]. In addition to MST1/2, mitogen-activated protein kinase kinase kinase (MAP3K) family members also can phosphorylate and activate LATS1/2 [28]. Activated LATS1/2 phosphorylate YAP/TAZ, which are bound to 14-3-3ζ proteins and sequestered in the cytoplasm, thereby inhibiting the transcriptional activity of YAP/TAZ [29,30]. Additionally, the phosphorylation of YAP can trigger ubiquitination and degradation mediated by β-transducing repeat-containing protein (β-TrCP) [31,32]. YAP can also be inactivated by binding to tight junction protein 2 (TJP2) and non-receptor protein tyrosine phosphatase 14 (PTPN14) [33,34]. Meanwhile, activated G protein-coupled receptors also can activate YAP function via the rho-GTPase signaling pathway [35].
In addition to phosphorylation, multiple post-translational modifications play a crucial role in regulating YAP/TAZ activity. For example, YAP undergoes methylation by methyltransferase complex containing SET domain 1A (SETD7), and its nuclear translocation activity is then blocked; thereby the oncogenic activity of YAP is dramatically inhibited [36]. The O-GlcNAc glycosylation of LATS2 activates YAP, promoting tumor growth [37]. The acetylation of LATS1 inhibits YAP phosphorylation and degradation, fostering the invasion and proliferation of cancer cells [38,39]. Thus, post-translational modifications serve as an important mechanism for fine-tuning YAP signaling pathways. Hippo signaling pathway activation leads to the removal of inactive YAP/TAZ factors from the cell nucleus, transforming this information into a signal that inhibits growth and development. Consequently, it effectively regulates cell number and organ size [40].

3. Role of the Hippo-YAP/TAZ Signaling Pathway in Primary Liver Cancer

The mammalian liver exhibits robust regenerative capability and rapidly grows to its original size after 70% of hepatectomy [41]. The Hippo signaling pathway not only regulates liver size but also promotes primary liver cancer primarily by influencing cell proliferation, autophagy, invasion and metastasis, tumor resistance, and the tumor microenvironment (Figure 1). Current research is predominantly centered on YAP and TAZ.

3.1. Cell Proliferation

Hepatocytes are highly regenerative, and liver homeostasis is maintained mainly by a balance between proliferation and apoptosis. When the Hippo pathway is inactivated (activation of YAP/TAZ), hepatocytes undergo uncontrolled proliferation, leading to abnormal liver growth and HCC [42]. The aberrant activation of hepatic YAP results in liver enlargement and HCC in MST1/2 double knockout (DKO) mice, whereas the inhibition of YAP expression restores normal liver growth [43]. In mice with c-Myc-induced HCC, the inactivation of the Hippo pathway significantly increases TAZ expression, and TAZ in turn inhibits apoptosis through the TAZ-BCL2L12 axis, thereby promoting c-Myc-dependent hepatocellular carcinoma [44]. Grijalva et al. performed 70% of liver resection and observed that the expression of YAP target genes is increased within 24 h when MST1/2 and LATS1/2 are inhibited. YAP levels and the expression of target genes return to the baseline level in approximately 7 days, when the liver grows to a normal size [45]. Ba et al. found that the overexpression of YAP is closely associated with oncogenic features, such as epithelial–mesenchymal transition (EMT) and anchorage-independent growth. YAP acts in concert with TEAD1 to stimulate the expression of EMT transcription factor Zeb1, proliferation, and EMT while weakening intercellular tight junctions, thereby enhancing the migratory and invasive capabilities of tumor cells [46].

3.2. Autophagy

Autophagy deficiency impedes YAP degradation, resulting in its nuclear accumulation. YAP serves as a pivotal factor for tissue remodeling and HCC induced by autophagy deficiency. YAP in the cytoplasm and the nucleus in the liver is considerably increased in mice lacking autophagy-related protein 7 (Atg7), contributing to liver enlargement and tumorigenesis [47]. YAP is markedly upregulated in chemotherapy-resistant liver cancer cell lines, and as feedback, can enhance drug resistance by suppressing autophagy-related cell death.

3.3. Tumor Invasion and Metastasis

YAP/TAZ are frequently overexpressed in liver cancer tissues, positively correlating with tumor vascular invasion and EMT, thereby accelerating liver cancer progression [48]. Knockout of TAZ in liver cancer cell lines increases E-cadherin expression and decreases N-cadherin expression. Additionally, the activities of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase-9 (MMP9) are diminished, suppressing EMT and the invasion of liver cancer [49]. In vitro and in vivo experiments demonstrated that the enzyme 2-AG diacylglycerol lipase alpha (DAGLA/2-AG) axis promoted HCC progression by significantly inhibiting LATS1 and YAP phosphorylation, promoting YAP nuclear translocation and activity and, as a result, regulating cell proliferation, invasion, and metastasis [50]. Moreover, Guan et al. found that MEISC/D promote HCC development and invasion via both the Hippo-YAP and Wnt/β-catenin signaling pathways, indicating that Hippo signaling can combine with other pathways to further promote HCC invasion [51].

3.4. The Tumor Microenvironment

The TME refers to the tissue milieu in which tumor cells proliferate and interact and plays a crucial role in promoting HCC growth, invasion, and immune evasion [52]. Key TME components include tumor-associated macrophages (TAMs), other immunosuppressive cells, and their secreted inflammatory factors. MST1/2 inactivation increases the production of proinflammatory cytokines, leading to the infiltration of a significant number of M1 or mixed M1/M2 macrophages into the liver and liver inflammation. This process creates the TME that contributes to liver cancer development [43].

4. The Hippo/YAP Pathway in Liver Cancer Drug Resistance

Drug resistance in hepatocarcinoma cells is highly intricate, operating by various mechanisms, including altering drug distribution and metabolism, influencing cell proliferation, and regulating the DNA damage response [53,54,55]. The Hippo signaling pathway plays a crucial role in governing cancer cell proliferation, metastasis, and drug resistance, and YAP activation may confer resistance to chemotherapy, radiotherapy, or immunotherapy [56,57].
DNA-damaging drugs, such as doxorubicin, target DNA replication to induce cytotoxic effects and eliminate tumor cells and are extensively used for liver cancer treatment. Research indicates that liver cancer resistance to DNA-damaging drugs is closely linked to YAP. In hepatocellular carcinoma cells, the overexpression of YAP enhances resistance to doxorubicin by activating the mitogen-activated protein kinase (MAPK) pathway [58]. Sophora japonica, a traditional Chinese medicine, increases the sensitivity of hepatocellular carcinoma cells to oxaliplatin by both promoting YAP phosphorylation and inhibiting YAP expression [59]. Dai et al. found that the hypoxic microenvironment induces the nuclear translocation and accumulation of YAP, which acts as a survival input to promote the chemoresistance of chemotherapeutic agent topoisomerase I inhibitor SN38 in HCC therapy [60]. Sorafenib is a primary chemotherapy agent for HCC treatment; however, tumor resistance diminishes its effectiveness in promoting apoptosis and inhibiting liver cancer cell proliferation and compromises patient survival. Research has established a close relationship between the expression level of YAP and the sensitivity of liver cancer cells to sorafenib. YAP can induce tumor recurrence and resistance by suppressing the ability of sorafenib to stimulate liver cancer cell apoptosis and ferroptosis while promoting liver tumor stem cell self-renewal [61].
In conclusion, more and more research indicates that the activation of the Hippo-YAP/TAZ signaling pathway contributes to the chemoresistance of many drugs in HCC therapy. Conversely, inhibiting this pathway has been shown to enhance cancer cell sensitivity to anticancer drugs. For example, Hao et al. found that dihydroartemisinin reduces lipid droplets through YAP to promote the effect of anti-PD-1 antibody on hepatocellular carcinoma [30]. Therefore, targeting the YAP signaling pathway represents a promising therapeutic strategy to counter chemotherapy resistance.
YAP is closely linked to various malignant behaviors of hepatocarcinoma cells, including proliferation, invasion, and drug resistance. Growing evidence indicates that YAP contributes to tumor resistance against anticancer therapies. YAP represents a promising target for the development of anti-hepatocarcinoma therapies by disrupting drug resistance. A combination of YAP inhibition and anti-hepatocarcinoma drugs may offer a novel strategy for tackling drug-resistant liver cancer.

5. Targeting the Hippo/YAP Signaling Pathway in Primary Liver Cancer

Inhibitors, which target the upstream kinases, are expected to activate YAP/TAZ. Several agents have been developed to alter YAP/TAZ expression, subcellular distribution, and activities, ultimately impeding tumor initiation and progression. Targeting the Hippo signaling pathway serves as a promising therapeutic strategy for treating primary liver cancer.

5.1. Targeting Upstream Kinases MST/LATS

MST or LATS can be activated by epithelial splicing regulatory protein-2 (ESRP2)/neurofibromin 2 (NF2), long non-coding RNA LOC107985656, WW and C2 domain-containing protein (WWC), and T-box transcription factor 3 (TBX3)/phospholipase D1 (PLD1) [62,63,64,65]. The activation of the MST/LATS cascade increases phosphorylation and subsequent proteasomal degradation of YAP/TAZ, which in turn, inhibits the occurrence of liver cancer. In contrast, RACGTPase activating protein 1 (RACGAP1) and GTP-binding protein family members Septin 6 (SEPT6) inhibit LATS phosphorylation, thus increasing YAP nuclear translocation and the expression of target genes and promoting liver cancer progression [66,67]. Agents that target MST/LATS to regulate YAP/TAZ are listed in Table 1.

5.2. Direct Regulation of YAP/TAZ

Expression levels and subcellular localization of YAP/TAZ govern target gene expressions, cell proliferation, apoptosis, and EMT, among others. These factors are linked to the onset and progression of tumors. Thus, elucidating targets, which regulate YAP/TAZ transcription, post-translational modifications, and subcellular localization, hold promise for developing targeted therapies for primary liver cancer.
The transcriptional activity of YAP/TAZ can be regulated by many molecules and stress. High-mobility group box 1 (HMGB1)/GA-binding protein alpha (GABPα), miR-1224/cyclic AMP (cAMP)-response element binding protein (CREB), lysine acetyltransferase 6A (KAT6A), microRNA-590-5p, and AT-rich interaction domain 1A (ARID1A) can increase YAP levels [68,69,70,71,72]. MicroRNA-9-3p and MicroRNA-125b suppress the migration and invasion of HCC cells by targeting TAZ [73,74]. C-X-C chemokine receptor type 4 (CXCR4)/ubiquitin domain-containing protein 1 (UBTD1) is involved in the proteasome-dependent degradation of YAP [75]. Ubiquitin-specific peptidase 10 (USP10) and Josephin domain-containing protein 2 (JOSD2) promote the proliferation of primary liver cancer by deubiquitinating and stabilizing YAP/TAZ [76,77]. Chen et al. found that pectrin beta non-erythrocytic 1 (SPTBN1) signaling pathway promotes YAP methylation, leading to YAP degradation and inactivation [36]. Insulin-like growth factor 1 receptor (IGF1R), histone lysine methyltransferase SET domain containing 1A (SETD1A), and programmed cell death 10 (PDCD10) are involved in YAP phosphorylation [78,79,80,81]. The piezo-type mechanosensitive ion channel component 1 (Piezo1)/mitogen-activated protein kinase (MAPK) pathway and fluid shear stress (FSS) can directly induce the translocation of YAP into the nucleus, enhancing hepatocellular carcinoma progression [82,83]. TNF receptor II/heterogeneous nuclear ribonuclear protein K (TNFR2–hnRNPK) directly stabilize YAP to regulate YAP target genes, therefore promoting HCC progression [84]. The molecules and stress involved in the direct regulation of YAP/TAZ are shown in Table 2.

6. Drugs Targeting Hippo/YAP Signaling in Primary Cancer Therapy

Currently, many drugs and small molecule inhibitors have been developed to target the Hippo/YAP signaling pathway and display anti-liver cancer potential.
Tadalafil, a PDE5 inhibitor, can inhibit YAP/TAZ by activating MST1/LATS1 [84]. α-hederin, a monodesmosidic triterpenoid saponin isolated from Fructus akebiae, inhibits the proliferation of HCC cells by activating MST1/LATS1 [85]. Evodiamine and homoharringtonine exert anti-tumor effects in HCC through activating MST1/2 and upregulating LATS1 phosphorylation, leading to the phosphorylation and inactivation of YAP [86,87]. Zhao et al. found that metformin directly activated MST1/2 and phosphorylated YAP1 in vitro, suggesting that metformin activates the Hippo signaling pathway to regulate interleukin-22 (IL-22) mediated HCC progression [88]. Liu et al. found that bioactive components of poplar propolis obtained from north China can inhibit the proliferation of human hepatocellular carcinoma HepG2 cells in a LATS2-dependent manner [89]. Zhu et al. found that CT-707, a multi-kinase inhibitor approved by the China FDA and currently in clinical trials, potently inhibits YAP. CT-707 demonstrates significant cytotoxicity against HCC cells, particularly under hypoxic conditions. Mechanistically, CT-707’s inhibition of YAP signaling is attributed to its disruption of hypoxia-activated insulin-like growth factor 1 receptor (IGF1R) [78]. Zhang et al. also found that corosolic acid can suppress liver cancer growth by decreasing the level of CDK19/YAP-mediated O-GlcNAcylation [90]. Trametes robiniophila Murr, a traditional Chinese herbal medicine, restrains the proliferation and migration of HCC cells via the downregulation of YAP and has been widely used in adjuvant therapies for HCC [91]. In addition, statins, such as fluvastatin and simvastatin, have been shown to reduce TAZ expression levels in Huh1 cells and suppress the expression of TAZ target genes CYR61 and CTGF, as a result, attenuating hepatocellular carcinoma cell proliferation [92]. Clinical studies demonstrated that statin prolongs recurrence-free survival in patients following HCC surgery. Drugs targeting Hippo/YAP signaling in primary cancer therapy are shown in Table 3.
The most effective approach to reducing YAP protein expression is by directly targeting YAP protein [93]. RNA interference technology has also been used to lower YAP mRNA levels in MST1/2-deficient mice, thereby decreasing YAP protein expression. Reduction in YAP protein has been shown to substantially decrease liver tumor burden in mice [94]. It is important to note that for YAP to be oncogenic, it must interact with downstream regulatory factors. The notch signaling pathway is known to promote abnormal proliferation in liver cancer. Inhibitors for the notch signaling pathway represent potential treatments for YAP-based liver cancer [95].

7. Discussion

It is evident that several commonly used clinical drugs or inhibitors can exert anti-liver cancer effects by modulating the Hippo-YAP/TAZ pathway, including hypoglycemic, lipid-lowering, anticancer medications and certain natural plant ingredients. This offers novel perspectives for clinical drug applications. However, the effectiveness of emerging drugs is still under investigation, and their efficacy repeatability and safety profiles require further exploration. Efficient and reliable methods for the clinical translation and safety evaluation of these drugs need extensive research and development. Moreover, drug combinations targeting the Hippo-YAP/TAZ pathway may improve the efficacy of primary liver cancer therapy, which is worth further research.
The pathogenesis of liver cancer remains incompletely understood. In recent years, the roles of cell signaling pathways in cancer formation and progression have received increasing attention. the Hippo signaling pathway is a key one, and it was initially hypothesized by international researchers in the 1990s. This pathway has been highly conserved across evolutionary contexts in terms of composition, biological function, and molecular mechanisms [96]. The Hippo signaling pathway, which was discovered through fruit fly studies, plays a critical role in regulating cell proliferation, apoptosis, and organ size. YAP, a key component of the pathway, is notably overexpressed in liver tumors as an oncogene candidate. It serves as a significant regulatory factor to promote the formation, development, and metastasis of liver cancer, making it a promising target for novel treatments against cancer.
The Hippo/YAP signaling pathway plays a pivotal role in regulating various aspects of primary liver cancer, including tumor cell proliferation, autophagy, invasion, metastasis, the tumor microenvironment, and targeted drug resistance. Notably, the high expression of YAP/TAZ is a crucial factor in the onset and progression of primary liver cancer. It is worth noting that in addition to the Hippo signaling pathway, matrix stiffening is one of the major risk factors for HCC and drives tumor progression. Ma et al. found that matrix stiffening facilitates liver cancer stem cell (CSC) stemness by increasing YAP activity, and the group also described a novel therapeutic strategy for eradicating CSCs and improving the efficiency of HCC treatment by targeting YAP [97]. Although Hippo signaling is widely involved in the progression and metastasis of primary liver cancer, recent research showed that cancer is a complex pathological ecosystem and merely approaching cancer from a molecular perspective may not address all cancer-related issues. Therefore, if cancer is viewed as a pathological ecosystem, some emerging disciplines and technologies, such as the application of the knowledge system and research methods of synthetic biology, may be of great help to the reconstruction/repair of damaged ecosystems, such as the microenvironment of diseased cells, and provide patients with more promising treatment strategies in the future [98].
Drugs that target the Hippo signaling pathway, particularly inhibitors of YAP and TAZ, have garnered significant attention in recent years. However, their efficacy and safety profiles require further validation through animal experiments and clinical trials. As our understanding of the key regulators of the Hippo signaling pathway expands, the network’s regulatory mechanisms diversify, including advancements in upstream kinase inhibition. With ongoing research, more regulatory pathways are anticipated to be elucidated, potentially broadening treatment strategies by targeting the Hippo signaling pathway. This development holds promise for the discovery of new therapeutic agents to enhance the efficacy of liver cancer treatments.
Nevertheless, currently, there are no YAP inhibitors with sufficient specificity. In the future, the research and development of YAP-selective inhibitors are essential for expanding options in anti-liver cancer drugs and clinical treatments. The Hippo/YAP pathway may interact with other liver cancer-related signaling pathways, including notch, Wnt, and UPR, thereby contributing to the onset and progression of liver cancer. Detailed mechanisms linking the Hippo signaling pathway to liver cancer formation require further exploration.

8. Conclusions

YAP/TAZ significantly impact the initiation, progression, metastasis, invasion, and drug sensitivity of liver cancer. A variety of molecules and pathways can influence the Hippo signaling pathway, thereby affecting how YAP/TAZ regulate liver cancer. Given that YAP/TAZ are crucial oncogenic factors, the dysregulation of the Hippo pathway is a key driver for tumorigenesis and malignant transformation. Therefore, exploring the Hippo-YAP/TAZ pathway offers a valuable opportunity for the development of new targeted therapies for liver cancer.

Author Contributions

Conceptualization, Y.W.; writing—original draft preparation, Y.W.; writing—review and editing, Y.W. and L.R.; visualization, Y.W. and L.R.; supervision, Y.W.; project administration, Y.W.; funding acquisition, Y.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China, grant number 82302069 to Yina Wang.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Mattiuzzi, C.; Lippi, G. Current Cancer Epidemiology. J. Epidemiol. Glob. Health 2019, 9, 217–222. [Google Scholar] [CrossRef] [PubMed]
  2. Craig, A.J.; von Felden, J.; Garcia-Lezana, T.; Sarcognato, S.; Villanueva, A. Tumour evolution in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 139–152. [Google Scholar] [CrossRef] [PubMed]
  3. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics. CA Cancer J. Clin. 2020, 70, 7–30. [Google Scholar] [CrossRef] [PubMed]
  4. Wang, L.; Piao, Y.; Guo, F.; Wei, J.; Chen, Y.; Dai, X.; Zhang, X. Current progress of pig models for liver cancer research. Biomed. Pharmacother. 2023, 165, 115256. [Google Scholar] [CrossRef]
  5. Patel, S.H.; Camargo, F.D.; Yimlamai, D. Hippo signaling in the liver regulates organ size, cell fate, and carcinogenesis. Gastroenterology 2017, 152, 533–545. [Google Scholar] [CrossRef]
  6. Kriz, V.; Korinek, V. Wnt, RSPO and Hippo Signaling in the Intestine and Intestinal Stem Cells. Genes 2018, 9, 20. [Google Scholar] [CrossRef]
  7. Liu, Y.; Wang, X.; Yang, Y. Hepatic Hippo signaling inhibits development of hepatocellular carcinoma. Clin. Mol. Hepatol. 2020, 26, 742–750. [Google Scholar] [CrossRef]
  8. Cunningham, R.; Hansen, C.G. The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer. Clin. Sci. 2022, 136, 197–222. [Google Scholar] [CrossRef]
  9. Ortega, á.; Vera, I.; Diaz, M.P.; Navarro, C.; Rojas, M.; Torres, W.; Parra, H.; Salazar, J.; Sanctis, J.D.; Bermúdez, V. The YAP/TAZ signaling pathway in the tumor microenvironment and carcinogenesis: Current knowledge and therapeutic promises. Int. J. Mol. Sci. 2021, 23, 430. [Google Scholar] [CrossRef]
  10. Huang, J.; Wu, S.; Barrera, J.; Matthews, K.; Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 2005, 122, 421–434. [Google Scholar] [CrossRef]
  11. Chan, S.W.; Lim, C.J.; Chen, L.; Chong, Y.F.; Huang, C.; Song, H.; Hong, W. The Hippo pathway in biological control and cancer development. J. Cell. Physiol. 2011, 226, 928–939. [Google Scholar] [CrossRef]
  12. Mranda, G.M.; Xiang, Z.P.; Liu, J.J.; Wei, T.; Ding, Y. Advances in prognostic and therapeutic targets for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Hippo signaling pathway. Front. Oncol. 2022, 12, 937957. [Google Scholar] [CrossRef] [PubMed]
  13. Justice, R.W.; Zilian, O.; Woods, D.F.; Noll, M.; Bryant, P.J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 1995, 9, 534–546. [Google Scholar] [CrossRef] [PubMed]
  14. Xu, C.Y.; Jiang, J.; An, Y.; Ye, P.F.; Zhang, C.C.; Sun, N.N.; Miao, S.N.; Chai, M.Q.; Liu, W.M.; Yang, M.; et al. Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway. Acta Pharmacol. Sin. 2024, 45, 1201–1213. [Google Scholar] [CrossRef]
  15. Lee, N.Y.; Choi, M.G.; Lee, E.J.; Koo, J.H. Interplay between YAP/TAZ and metabolic dysfunction-associated steatotic liver disease progression. Arch. Pharm. Res. 2024, 47, 558–570. [Google Scholar] [CrossRef]
  16. Kumar, R.; Hong, W. Hippo Signaling at the Hallmarks of Cancer and Drug Resistance. Cells 2024, 13, 564. [Google Scholar] [CrossRef] [PubMed]
  17. Zhao, M.; Zhang, Y.; Jiang, Y.; Wang, K.; Wang, X.; Zhou, D.; Wang, Y.; Yu, R.; Zhou, X. YAP promotes autophagy and progression of gliomas via upregulating HMGB1. J. Exp. Clin. Cancer Res. 2021, 40, 99. [Google Scholar] [CrossRef] [PubMed]
  18. Mao, W.; Mai, J.; Peng, H.; Wan, J.; Sun, T. YAP in pancreatic cancer: Oncogenic role and therapeutic strategy. Theranostics 2021, 11, 1753–1762. [Google Scholar] [CrossRef]
  19. Hayashi, H.; Higashi, T.; Yokoyama, N.; Kaida, T.; Sakamoto, K.; Fukushima, Y.; Ishimoto, T.; Kuroki, H.; Nitta, H.; Hashimoto, D.; et al. An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem cell-like behaviors contributing to disease progression. Cancer Res. 2015, 75, 4985–4997. [Google Scholar] [CrossRef]
  20. Wu, H.; Liu, Y.; Jiang, X.W.; Li, W.F.; Guo, G.; Gong, J.P.; Ding, X. Clinicopathological and prognostic significance of Yes- associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma. Tumour Biol. 2016, 37, 13499–13508. [Google Scholar] [CrossRef]
  21. Nishio, M.; Hamada, K.; Kawahara, K.; Sasaki, M.; Noguchi, F.; Chiba, S.; Mizuno, K.; Suzuki, S.O.; Dong, Y.; Tokuda, M.; et al. Cancer susceptibility and embryonic lethality in Mobla/lb double-mutant mice. J. Clin. Investig. 2012, 122, 4505–4518. [Google Scholar] [CrossRef]
  22. Leask, A.; Nguyen, J.; Naik, A.; Chitturi, P.; Riser, B.L. The role of yes activated protein (YAP) in melanoma metastasis. iScience 2024, 27, 109864. [Google Scholar] [CrossRef]
  23. Felley-Bosco, E.; Stahel, R. Hippo/YAP pathway for targeted therapy. Transl. Lung Cancer Res. 2014, 3, 75–83. [Google Scholar] [PubMed]
  24. Qi, S.; Zhu, Y.; Liu, X.; Li, P.; Wang, Y.; Zeng, Y.; Yu, A.; Wang, Y.; Sha, Z.; Zhong, Z.; et al. WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy. Mol. Cell 2022, 82, 1850–1864. [Google Scholar] [CrossRef] [PubMed]
  25. Chan, E.H.; Nousiainen, M.; Chalamalasetty, R.B.; Schäfer, A.; Nigg, E.A.; Silljé, H.H. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 2005, 24, 2076–2086. [Google Scholar] [CrossRef]
  26. Dhanaraman, T.; Singh, S.; Killoran, R.C.; Singh, A.; Xu, X.; Shifman, J.M.; Smith, M.J. RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway. Sci. Signal. 2020, 13, eabb4778. [Google Scholar] [CrossRef]
  27. Delgado, I.L.S.; Carmona, B.; Nolasco, S.; Santos, D.; Leitão, A.; Soares, H. MOB: Pivotal conserved proteins in cytokinesis, cell architecture and tissue homeostasis. Biology 2020, 9, 413. [Google Scholar] [CrossRef] [PubMed]
  28. Meng, Z.; Moroishi, T.; Mottier-Pavie, V.; Plouffe, S.W.; Hansen, C.G.; Hong, A.W.; Park, H.W.; Mo, J.S.; Lu, W.; Lu, S.; et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat. Commun. 2015, 6, 8357. [Google Scholar] [CrossRef]
  29. Li, F.L.; Fu, V.; Liu, G.; Tang, T.; Konradi, A.W.; Peng, X.; Kemper, E.; Cravatt, B.F.; Franklin, J.M.; Wu, Z.; et al. Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides. Nat. Chem. Biol. 2022, 18, 1076–1086. [Google Scholar] [CrossRef]
  30. Hao, X.; Zhang, Y.; Shi, X.; Liu, H.; Zheng, Z.; Han, G.; Rong, D.; Zhang, C.; Tang, W.; Wang, X. CircPAK1 promotes the progression of hepatocellular carcinoma via modulation of YAP nucleus localization by interacting with 14-3-3ζ. J. Exp. Clin. Cancer Res. 2022, 41, 281. [Google Scholar] [CrossRef] [PubMed]
  31. Zhao, B.; Li, L.; Tumaneng, K.; Wang, C.Y.; Guan, K.L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF (β-TRCP). Genes Dev. 2010, 24, 72–85. [Google Scholar] [CrossRef] [PubMed]
  32. Liu, C.Y.; Zha, Z.Y.; Zhou, X.; Zhang, H.; Huang, W.; Zhao, D.; Li, T.; Chan, S.W.; Lim, C.J.; Hong, W.; et al. The Hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF β-TrCP E3 ligase. J. Biol. Chem. 2010, 285, 37159–37169. [Google Scholar] [CrossRef] [PubMed]
  33. Liu, X.; Yang, N.; Figel, S.A.; Wilson, K.E.; Morrison, C.D.; Gelman, I.H.; Zhang, J. PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene 2013, 32, 1266–1273. [Google Scholar] [CrossRef] [PubMed]
  34. Oka, T.; Remue, E.; Meerschaert, K.; Vanloo, B.; Boucherie, C.; Gfeller, D.; Bader, G.D.; Sidhu, S.S.; Vandekerckhove, J.; Gettemans, J.; et al. Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling. Biochem. J. 2010, 432, 461–472. [Google Scholar] [CrossRef]
  35. Feng, X.; Degese, M.S.; Iglesias-Bartolome, R.; Vaque, J.P.; Molinolo, A.A.; Rodrigues, M.; Zaidi, M.R.; Ksander, B.R.; Merlino, G.; Sodhi, A.; et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 2014, 25, 831–845. [Google Scholar] [CrossRef] [PubMed]
  36. Chen, S.; Wu, H.; Wang, Z.; Jia, M.; Guo, J.; Jin, J.; Li, X.; Meng, D.; Lin, L.; He, A.R.; et al. Loss of SPTBN1 suppresses autophagy via SETD7-mediated YAP methylation in hepatocellular carcinoma initiation and development. Cell. Mol. Gastroenterol. Hepatol. 2022, 13, 949–973.e7. [Google Scholar] [CrossRef]
  37. Zhai, L.; Yang, X.; Dong, J.; Qian, L.; Gao, Y.; Lv, Y.; Chen, L.; Chen, B.; Zhou, F. O-GlcNAcylation mediates endometrial cancer progression by regulating the Hippo-YAP pathway. Int. J. Oncol. 2023, 63, 90. [Google Scholar] [CrossRef] [PubMed]
  38. Kim, E.; Kang, J.G.; Kang, M.J.; Park, J.H.; Kim, Y.J.; Kweon, T.H.; Lee, H.W.; Jho, E.H.; Lee, Y.H.; Kim, S.I.; et al. O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity. Proc. Natl. Acad. Sci. USA 2020, 117, 14259–14269. [Google Scholar] [CrossRef]
  39. Yang, S.; Xu, W.; Liu, C.; Jin, J.; Li, X.; Jiang, Y.; Zhang, L.; Meng, X.; Zhan, J.; Zhang, H. LATS1 K751 acetylation blocksactivation of Hippo signalling and switches LATS1 from a tumor suppressor to an oncoprotein. Sci. China Life Sci. 2022, 65, 129–141. [Google Scholar] [CrossRef]
  40. Zhao, B.; Tumaneng, K.; Guan, K.L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat. Cell Biol. 2011, 13, 877–883. [Google Scholar] [CrossRef]
  41. de Haan, L.R.; van Golen, R.F.; Heger, M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol. Rev. 2024, 76, 500–558. [Google Scholar] [CrossRef]
  42. Yu, F.X.; Meng, Z.; Plouffe, S.W.; Guan, K.L. Hippo pathway regulation of gastrointestinal tissues. Ann. Rev. Physiol. 2015, 77, 201–227. [Google Scholar] [CrossRef]
  43. Kim, W.; Khan, S.K.; Liu, Y.; Xu, R.; Park, O.; He, Y.; Cha, B.; Yang, Y. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut 2018, 67, 1692–1703. [Google Scholar] [CrossRef] [PubMed]
  44. Wang, H.; Zhang, S.; Zhang, Y.; Jia, J.; Wang, J.; Liu, X.; Zhang, J.; Song, X.; Ribback, S.; Cigliano, A.; et al. TAZ is indispensable for c-MYC-induced hepatocarcinogenesis. J. Hepatol. 2022, 76, 123–134. [Google Scholar] [CrossRef]
  45. Grijalva, J.L.; Huizenga, M.; Mueller, K.; Rodriguez, S.; Brazzo, J.; Camargo, F.; Sadri-Vakili, G.; Vakili, K. Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol. 2014, 307, G196–G204. [Google Scholar] [CrossRef] [PubMed]
  46. Ba, M.C.; Long, H.; Cui, S.Z.; Tang, Y.Q.; Wu, Y.B.; Zhang, X.L.; Tang, H.S.; Bai, S.X. Multivariate comparison of B-ultrasound guided and laparoscopic continuous circulatory hyperthermic intraperitoneal perfusion chemotherapyfor malignant ascites. Surg. Endosc. 2013, 27, 2735–2743. [Google Scholar] [CrossRef] [PubMed]
  47. Lee, Y.A.; Noon, L.A.; Akat, K.M.; Ybanez, M.D.; Lee, T.F.; Berres, M.L.; Fujiwara, N.; Goossens, N.; Chou, H.I.; Parvin-Nejad, F.P.; et al. Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap. Nat. Commun. 2018, 9, 4962. [Google Scholar] [CrossRef]
  48. Park, H.; Lee, Y.; Lee, K.; Lee, H.; Yoo, J.E.; Ahn, S.; Park, Y.N.; Kim, H. The clinicopathological significance of YAP/TAZ expression in hepatocellular carcinoma with relation to hypoxia and stemness. Pathol. Oncol. Res. 2021, 27, 604600. [Google Scholar] [CrossRef]
  49. Xiao, H.; Jiang, N.; Zhou, B.; Liu, Q.; Du, C. TAZ regulates cell proliferation and epithelial-mesenchymal transition of human hepatocellular carcinoma. Cancer Sci. 2015, 106, 151–159. [Google Scholar] [CrossRef]
  50. Yan, Y.C.; Meng, G.X.; Yang, C.C.; Yang, Y.F.; Tan, S.Y.; Yan, L.J.; Ding, Z.N.; Ma, Y.L.; Dong, Z.R.; Li, T. Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity. Cell Death Dis. 2023, 14, 404. [Google Scholar] [CrossRef]
  51. Guan, L.; Li, T.; Ai, N.; Wang, W.; He, B.; Bai, Y.; Yu, Z.; Li, M.; Dong, S.; Zhu, Q.; et al. MEIS2C and MEIS2D promote tumor progression via Wnt/beta-catenin and hippo/YAP signaling in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 2019, 38, 417. [Google Scholar] [CrossRef]
  52. Lu, C.; Rong, D.; Zhang, B.; Zheng, W.; Wang, X.; Chen, Z.; Tang, W. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: Challenges and opportunities. Mol. Cancer 2019, 18, 130. [Google Scholar] [CrossRef] [PubMed]
  53. Su, X.; Li, Y.; Ren, Y.; Cao, M.; Yang, G.; Luo, J.; Hu, Z.; Deng, H.; Deng, M.; Liu, B.; et al. A new strategy for overcoming drug resistance in liver cancer: Epigenetic regulation. Biomed. Pharmacother. 2024, 176, 116902. [Google Scholar] [CrossRef] [PubMed]
  54. Huang, P.S.; Wang, L.Y.; Wang, Y.W.; Tsai, M.M.; Lin, T.K.; Liao, C.J.; Yeh, C.T.; Lin, K.H. Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer. Cells 2023, 12, 869. [Google Scholar] [CrossRef] [PubMed]
  55. Nussinov, R.; Tsai, C.J.; Jang, H. Anticancer drug resistance: An update and perspective. Drug Resist. Updat. 2021, 59, 100796. [Google Scholar] [CrossRef]
  56. Thompson, B.J. YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy. Bioessays 2020, 5, e1900162. [Google Scholar] [CrossRef]
  57. Mohajan, S.; Jaiswal, P.K.; Vatanmakarian, M.; Yousefi, H.; Sankaralingam, S.; Alahari, S.K.; Koul, S.; Koul, H.K. Hippo pathway: Regulation, deregulation and potential therapeutic targets in cancer. Cancer Lett. 2021, 507, 112–123. [Google Scholar] [CrossRef]
  58. Huo, X.; Zhang, Q.; Liu, A.M.; Tang, C.; Gong, Y.; Bian, J.; Luk, J.M.; Xu, Z.; Chen, J. Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellular carcinoma. Oncol. Rep. 2013, 29, 840–846. [Google Scholar] [CrossRef]
  59. Tao, Y.; Shan, L.; Xu, X.; Jiang, H.; Chen, R.; Qian, Z.; Yang, Z.; Liang, B.; Zheng, H.; Cai, F.; et al. Huaier augmented the chemotherapeutic sensitivity of oxaliplatin via downregulation of YAP in hepatocellular carcinoma. J. Cancer 2018, 93, 962–3970. [Google Scholar] [CrossRef]
  60. Dai, X.Y.; Zhuang, L.H.; Wang, D.D.; Zhou, T.Y.; Chang, L.L.; Gai, R.H.; Zhu, D.F.; Yang, B.; Zhu, H.; He, Q.J. Nuclear translocation and activation of YAP by hypoxia contributes to the chemoresistance of SN38 in hepatocellular carcinoma cells. Oncotarget 2016, 7, 6933–6947. [Google Scholar] [CrossRef]
  61. Sun, T.; Mao, W.; Peng, H.; Wang, Q.; Jiao, L. YAP promotes sorafenib resistance in hepatocellular carcinoma by upregulating surviving. Cell. Oncol. 2021, 44, 689–699. [Google Scholar] [CrossRef]
  62. Hyun, J.; Al, A.M.; Dutta, R.K.; Oh, S.H.; Xiang, K.; Zhou, X.; Maeso-Díaz, R.; Caffrey, R.; Sanyal, A.J.; Freedman, J.A.; et al. Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease. J. Hepatol. 2021, 75, 623–633. [Google Scholar] [CrossRef] [PubMed]
  63. Zeng, Y.; Xu, Q.; Xu, N. Long non-coding RNA LOC107985656 represses the proliferation of hepatocellular carcinoma cells through activation of the tumor-suppressive Hippo pathway. Bioengineered 2021, 12, 7964–7974. [Google Scholar] [CrossRef] [PubMed]
  64. Höffken, V.; Hermann, A.; Pavenstädt, H.; Kremerskothen, J. WWC Proteins: Important Regulators of Hippo Signaling in Cancer. Cancers 2021, 13, 306. [Google Scholar] [CrossRef] [PubMed]
  65. Liang, B.; Zhou, Y.; Qian, M.; Xu, M.; Wang, J.; Zhang, Y.; Song, X.; Wang, H.; Lin, S.; Ren, C.; et al. TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis. J. Hepatol. 2021, 75, 120–131. [Google Scholar] [CrossRef]
  66. Yang, X.M.; Cao, X.Y.; He, P.; Li, J.; Feng, M.X.; Zhang, Y.L.; Zhang, X.L.; Wang, Y.H.; Yang, Q.; Zhu, L.; et al. Overexpression of Rac GTPase Activating Protein 1 Contributes to Proliferation of Cancer Cells by Reducing Hippo Signaling to Promote Cytokinesis. Gastroenterology 2018, 155, 1233–1249.e22. [Google Scholar] [CrossRef]
  67. Fan, Y.; Du, Z.; Ding, Q.; Zhang, J.; Op, d.w.m.; Gerbes, A.L.; Liu, M.; Steib, C.J. SEPT6 drives hepatocellular carcinoma cell proliferation, migration and invasion via the Hippo/YAP signaling pathway. Int. J. Oncol. 2021, 58, 25. [Google Scholar] [CrossRef]
  68. Chen, R.; Zhu, S.; Fan, X.G.; Wang, H.; Lotze, M.T.; Zeh, H.J.; Billiar, T.R.; Kang, R.; Tang, D. High mobility group protein B1 controls liver cancer initiation through yes-associated protein-dependent aerobic glycolysis. Hepatology 2018, 67, 1823–1841. [Google Scholar] [CrossRef] [PubMed]
  69. Yang, S.; Jiang, W.; Yang, W.; Yang, C.; Yang, X.; Chen, K.; Hu, Y.; Shen, G.; Lu, L.; Cheng, F.; et al. Epigenetically modulated miR-1224 suppresses the proliferation of HCC through CREB-mediated activation of YAP signaling pathway. Mol. Ther. Nucleic Acids 2021, 23, 944–958. [Google Scholar] [CrossRef]
  70. Jin, Y.; Yang, R.; Ding, J.; Zhu, F.; Zhu, C.; Xu, Q.; Cai, J. KAT6A is associated with sorafenib resistance and contributes to progression of hepatocellular carcinoma by targeting YAP. Biochem. Biophys. Res. Commun. 2021, 585, 185–190. [Google Scholar] [CrossRef]
  71. Chen, M.; Wu, L.; Tu, J.; Zhao, Z.; Fan, X.; Mao, J.; Weng, Q.; Wu, X.; Huang, L.; Xu, M.; et al. miR-590-5p suppresses hepatocellular carcinoma chemoresistance by targeting YAP1 expression. EBioMedicine 2018, 35, 142–154. [Google Scholar] [CrossRef]
  72. Driskill, J.H.; Pan, D. The Hippo pathway in liver homeostasis and pathophysiology. Annu. Rev. Pathol. Mech. 2021, 16, 299–322. [Google Scholar] [CrossRef]
  73. Higashi, T.; Hayashi, H.; Ishimoto, T.; Takeyama, H.; Kaida, T.; Arima, K.; Taki, K.; Sakamoto, K.; Kuroki, H.; Okabe, H. miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells. Br. J. Cancer 2015, 113, 252–258. [Google Scholar] [CrossRef] [PubMed]
  74. Li, J.; Fang, L.; Yu, W.; Wang, Y. MicroRNA-125b suppresses the migration and invasion of hepatocellular carcinoma cells by targeting transcriptional coactivator with PDZ-binding motif. Oncol. Lett. 2015, 9, 1971–1975. [Google Scholar] [CrossRef]
  75. Yang, N.; Chen, T.; Wang, L.; Liu, R.; Niu, Y.; Sun, L.; Yao, B.; Wang, Y.; Yang, W.; Liu, Q.; et al. CXCR4 mediates matrix stiffness-induced downregulation of UBTD1 driving hepatocellular carcinoma progression via YAP signaling pathway. Theranostics 2020, 10, 5790–5801. [Google Scholar] [CrossRef]
  76. Zhu, H.; Yan, F.; Yuan, T.; Qian, M.; Zhou, T.; Dai, X.; Cao, J.; Ying, M.; Dong, X.; He, Q.; et al. USP10 promotes proliferation of hepatocellular carcinoma by deubiquitinating and stabilizing YAP/TAZ. Cancer Res. 2020, 80, 2204–2216. [Google Scholar] [CrossRef]
  77. Qian, M.; Yan, F.; Wang, W.; Du, J.; Yuan, T.; Wu, R.; Zhao, C.; Wang, J.; Lu, J.; Zhang, B.; et al. Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression. Acta Pharm. Sin. B 2021, 11, 4008–4019. [Google Scholar] [CrossRef] [PubMed]
  78. Zhu, H.; Wang, D.D.; Yuan, T.; Yan, F.J.; Zeng, C.M.; Dai, X.Y.; Chen, Z.B.; Chen, Y.; Zhou, T.; Fan, G.H.; et al. Multikinase inhibitor CT-707 targets liver cancer by interrupting the hypoxia-activated IGF-1R-YAP axis. Cancer Res. 2018, 78, 3995–4006. [Google Scholar] [CrossRef]
  79. Wu, J.; Chai, H.; Li, F.; Ren, Q.; Gu, Y. SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma. Life Sci. 2020, 260, 118406. [Google Scholar] [CrossRef] [PubMed]
  80. Sun, B.; Zhong, F.J.; Xu, C.; Li, Y.M.; Zhao, Y.R.; Cao, M.M.; Yang, L.Y. Programmed cell death 10 promotes metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma via PP2Ac-mediated YAP activation. Cell Death Dis. 2021, 12, 849. [Google Scholar] [CrossRef]
  81. Liu, S.; Xu, X.; Fang, Z.; Ning, Y.; Deng, B.; Pan, X.; He, Y.; Yang, Z.; Huang, K.; Li, J. Piezo1 impairs hepatocellular tumor growth via deregulation of the MAPK-mediated YAP signaling pathway. Cell Calcium 2021, 95, 102367. [Google Scholar] [CrossRef]
  82. Yu, H.; He, J.; Su, G.; Wangl, Y.; Fang, F.; Yang, W.; Gu, K.; Fu, N.; Wang, Y.; Shen, Y.; et al. Fluid shear stress activates YAP to promote epithelial-mesenchymal transition in hepatocellular carcinoma. Mol. Oncol. 2021, 15, 3164–3183. [Google Scholar] [CrossRef] [PubMed]
  83. Meng, Y.; Zhao, Q.; An, L.; Jiao, S.; Li, R.; Sang, Y.; Liao, J.; Nie, P.; Wen, F.; Ju, J.; et al. A TNFR2-hnRNPK axis promotes primary liver cancer development via activation of YAP signaling in hepatic progenitor cells. Cancer Res. 2021, 81, 3036–3050. [Google Scholar] [CrossRef] [PubMed]
  84. Kong, D.; Jiang, Y.; Miao, X.; Wu, Z.; Liu, H.; Gong, W. Tadalafil enhances the therapeutic efficacy of BET inhibitors in hepatocellular carcinoma through activating Hippo pathway. Biochim. Biophys. Acta Mol. Basis Dis. 2021, 1867, 166267. [Google Scholar] [CrossRef]
  85. Chen, T.; Sun, D.; Wang, Q.; Zhou, T.; Tan, J.; Xu, C.; Cheng, H.; Shen, W. α-Hederin inhibits the proliferation of hepatocellular carcinoma cells via Hippo-Yes-associated protein signaling pathway. Front. Oncol. 2022, 12, 839603. [Google Scholar] [CrossRef]
  86. Zhao, S.; Xu, K.; Jiang, R.; Li, D.Y.; Guo, X.X.; Zhou, P.; Tang, J.F.; Li, L.S.; Zeng, D.; Hu, L.; et al. Evodiamine inhibits proliferation and promotes apoptosis of hepatocellular carcinoma cells via the Lippo-Yes-Associated protein signaling pathway. Front. Oncol. 2022, 12, 839603. [Google Scholar]
  87. Wang, H.; Wang, R.; Huang, D.; Li, S.; Gao, B.; Kang, Z.; Tang, B.; Xie, J.; Yan, F.; Liang, R.; et al. Homoharringtonine exerts anti-tumor effects in hepatocellular carcinoma through activation of the Hippo pathway. Front. Pharmacol. 2021, 12, 592071. [Google Scholar] [CrossRef]
  88. Zhao, D.; Xia, L.; Geng, W.; Xu, D.; Zhong, C.; Zhang, J.; Xia, Q. Metformin suppresses interleukin-22 induced hepatocellular carcinoma by upregulating Hippo signaling pathway. J. Gastroenterol. Hepatol. 2021, 36, 3469–3476. [Google Scholar] [CrossRef]
  89. Liu, H.; Li, J.; Yuan, W.; Hao, S.; Wang, M.; Wang, F.; Xuan, H. Bioactive components and mechanisms of poplar propolis in inhibiting proliferation of human hepatocellular carcinoma HepG2 cells. Biomed. Pharmacother. 2021, 144, 112364. [Google Scholar] [CrossRef] [PubMed]
  90. Zhang, C.; Niu, Y.; Wang, Z.; Xu, X.; Li, Y.; Ma, L.; Wang, J.; Yu, Y. Corosolic acid inhibits cancer progression by decreasing the level of CDK19-mediated O-GlcNAcylation in liver cancer cells. Cell Death Dis. 2021, 12, 889. [Google Scholar] [CrossRef]
  91. Shan, L.; Li, Y.; Jiang, H.; Tao, Y.; Qian, Z.; Li, L.; Cai, F.; Ma, L.; Yu, Y. Huaier restrains proliferative and migratory potential of hepatocellular carcinoma cells partially through decreased Yes-associated protein 1. J. Cancer 2017, 8, 4087–4097. [Google Scholar] [CrossRef] [PubMed]
  92. Higashi, T.; Hayashi, H.; Kitano, Y.; Yamamura, K.; Kaida, T.; Arima, K.; Taki, K.; Nakagawa, S.; Okabe, H.; Nitta, H.; et al. Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma. Med. Oncol. 2016, 33, 123. [Google Scholar] [CrossRef] [PubMed]
  93. Zanconato, F.; Cordenonsi, M.; Piccolo, S. YAP/TAZ at the roots of cancer. Cancer Cell 2016, 29, 783–803. [Google Scholar] [CrossRef] [PubMed]
  94. Fitamant, J.; Kottakis, F.; Benhamouche, S.; Tian, H.S.; Chuvin, N.; Parachoniak, C.A.; Nagle, J.M.; Perera, R.M.; Lapouge, M.; Deshpande, V.; et al. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression. Cell Rep. 2015, 10, 1692–1707. [Google Scholar] [CrossRef]
  95. Yimlamai, D.; Christodoulou, C.; Galli, G.G.; Yanger, K.; Pepe-Mooney, B.; Gurung, B.; Shrestha, K.; Cahan, P.; Stanger, B.Z.; Camargo, F.D. Hippo pathway activity influences liver cell fate. Cell 2014, 157, 1324–1338. [Google Scholar] [CrossRef]
  96. Lin, K.C.; Park, H.W.; Guan, K.L. Regulation of the Hippo Pathway Transcription Factor TEAD. Trends Biochem. Sci. 2017, 42, 862–872. [Google Scholar] [CrossRef]
  97. Ma, D.; Luo, Q.; Song, G. Matrix stiffening facilitates stemness of liver cancer stem cells by YAP activation and BMF inhibition. Biomater. Adv. 2024, 163, 213936. [Google Scholar] [CrossRef]
  98. Luo, W. Nasopharyngeal carcinoma ecology theory: Cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem. Theranostics 2023, 13, 1607–1631. [Google Scholar] [CrossRef]
Onco 04 00016 g001
Figure 1. Role of the Hippo-YAP/TAZ signaling pathway in primary liver cancer. YAP/TAZ: Yes-associated protein/transcriptional coactivator with PDZ-binding motif; MST1/2: Ste20-like kinases 1/2; LATS1/2: large tumor suppressor 1/2; CTGF: connective tissue growth factor; CYR61: cysteine-rich 61. This Figure was created with BioRender.com.
Figure 1. Role of the Hippo-YAP/TAZ signaling pathway in primary liver cancer. YAP/TAZ: Yes-associated protein/transcriptional coactivator with PDZ-binding motif; MST1/2: Ste20-like kinases 1/2; LATS1/2: large tumor suppressor 1/2; CTGF: connective tissue growth factor; CYR61: cysteine-rich 61. This Figure was created with BioRender.com.
Onco 04 00016 g001
Table 1. The molecules involved in indirect regulation of YAP/TAZ by targeting the MST/LATS.
Table 1. The molecules involved in indirect regulation of YAP/TAZ by targeting the MST/LATS.
StatusMoleculesTargetsFunction
Hippo onESRP2/NF2 MST1/2Loss of ESRP2/NF2 function permits sustained YAP/TAZ activity that drives hepatocyte proliferation, advantaging the growth of cells with mutations that enable them to survive chronic oncogenic stress [62].
lncRNA LOC107985656/miR-106b-5pLATS1LOC107985656 regulated the expression of LATS1 by acting as a sponge for absorbing miR-106b-5p in HCC cells [63].
WWCLATS1/2WWC proteins positively regulate the Hippo pathway via the activation of LATS1/2 kinases and the subsequent cytoplasmic accumulation of phosphorylated YAP [64].
TBX3/PLD1LATS2TBX3 inhibited HCC cell growth, as well as YAP/TAZ activation, by promoting the overexpression of LATS2 via suppressing transcriptional target PLD1 [65].
Hippo offRACGAP1LATS1/2RACGAP1 promotes the proliferation of HCC cells by reducing the activation of LATS1/2 [66].
SEPT6LATS1SEPT6 facilitates F-actin formation, which induces LATS1 dephosphorylation, inhibits Hippo signaling, and upregulates YAP expression and nuclear translocation [67].
Table 2. The molecules involved in direct regulation of transcriptional coactivators YAP/TAZ.
Table 2. The molecules involved in direct regulation of transcriptional coactivators YAP/TAZ.
Regulation LevelMoleculesFunction
TranscriptionHMGB1/GABPαThe binding of HMGB1 to GABPα promotes the expression YAP at the transcriptional level [68].
miR-1224/CREBBy binding with CREB, miR-1224 could repress the transcription and the activation of YAP [69].
KAT6AKAT6A was associated with sorafenib resistance and contributes to the progression of HCC by targeting YAP expression [70].
miR-590-5pYAP is regulated by microRNA-590-5p and is critical for HCC chemoresistance by regulating the expression of stemness markers and ATP-binding cassette transporters [70].
ARID1A (AT-rich interaction domain 1A)ARID1A was discovered to bind to YAP, inhibiting its transcriptional output [72].
TranslationMicroRNA-9-3pMicroRNA-9-3p acts as a tumor suppressor miR by targeting TAZ expression in HCC cells [73].
MicroRNA-125bmiR-125b may be involved in the tumorigenesis of HCC at least in part by the suppression of TAZ [74].
UbiquitinationCXCR4/UBTD1CXCR4 decreases the levels of UBTD1, which is involved in the proteasome-dependent degradation of YAP [75].
USP10USP10 promotes the proliferation of hepatocellular carcinoma by deubiquitinating and stabilizing YAP/TAZ [76].
JOSD2Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression [77].
MethylationSPTBN1/SETD7SPTBN1 positively regulated the expression of the suppressor of SETD7 to promote YAP methylation, which leads to YAP degradation and inactivation [36].
PhosphorylationIGF1RThe depletion of IGF1R increased the p-YAP, which denoted the loss of YAP function [78].
SETD1ASETD1A deficiency impairs YAP phosphorylation and activation. In contrast, SETD1A enhances YAP activation to induce sorafenib primary resistance in HCC [79].
PDCD10PDCD10 directly binds to the catalytic subunit of protein phosphatase 2A (PP2Ac) and increases its enzymatic activity, leading to dephosphorylation of the YAP, which contributes to YAP nuclear translocation and transcriptional activation [80].
Nucleus translocationPiezo1/MAPKPiezo1 activates the mitogen-activated protein kinase (MAPK) pathway and then integrates with YAP signaling to control the nuclear translocation of YAP and the regulation of its target genes [81].
FSSFSS induces the translocation of YAP from the cytomembrane to the nucleus, contributes to epithelial–mesenchymal transition (EMT), and enhances metastasis in hepatocellular carcinoma [82].
StabilizationTNFR2–hnRNPKTNFR2–hnRNPK acted downstream of TNFα–TNFR2 signaling to directly interact with and stabilize YAP on target gene promoters genome-wide, therefore coregulating the expression of YAP target genes [83].
Table 3. Drugs targeting Hippo/YAP signaling in primary cancer therapy.
Table 3. Drugs targeting Hippo/YAP signaling in primary cancer therapy.
TargetDrugFunction
MST1/LATS1TadalafilTadalafil blocks YAP/TAZ protein expression by activating the Hippo pathway and enhances the therapeutic efficacy of BET inhibitors in hepatocellular carcinoma treatment [84].
α-Hederinα-Hederin treatment effectively enhanced MST1 and LATS1 gene expression while downregulated YAP gene expression in HepG2 and SMMC-7721 cells [85].
MST1/2 and LATS1EvodiamineEvodiamine activates MST1/2 and upregulates LATS1 phosphorylation, leading to phosphorylation and decreased nuclear translocation of YAP [86].
HomoharringtonineHomoharringtonine treatment increased the phosphorylation levels of MST1/2 and LATS1, significantly inhibiting HCC cell growth by suppressing cell proliferation and colony formation [87].
MST1/2 and LATS1/2 MetforminMetformin directly inhibits LATS1/2 and activates MST1/2, phosphorylating YAP1, as a result, suppressing IL-22-mediated HCC progression [88].
LATS2Poplar propolisPoplar propolis obviously upregulated the levels of LATS2 and decreased the expression of YAP, TAZ, and their target protein in the nucleus [89].
YAPCT-707CT-707 has remarkable inhibitory activity against YAP function and exhibits prominent cytotoxicity under hypoxia on HCC cells [78].
Corosolic acid Corosolic acid can reduce YAP expression and O-GlcNAcylation by inhibiting the activity of CDK19 [90].
Trametes robiniophila MurrTrametes robiniophila Murr treatment translocated YAP from the nucleus to the cytoplasm and further promoted the phosphorylation of YAP to be degraded by ubiquitination [91].
TAZStatin (fluvastatin and simvastatin)TAZ expression was suppressed in HCC cells by fluvastatin and simvastatin treatment, which have anti-proliferative effects, induced apoptosis in HCC cells, and improved the prognosis of HCC patients [92].
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Wang, Y.; Rui, L. Targeting the Hippo- Yes-Associated Protein/Transcriptional Coactivator with PDZ-Binding Motif Signaling Pathway in Primary Liver Cancer Therapy. Onco 2024, 4, 217-231. https://doi.org/10.3390/onco4030016

AMA Style

Wang Y, Rui L. Targeting the Hippo- Yes-Associated Protein/Transcriptional Coactivator with PDZ-Binding Motif Signaling Pathway in Primary Liver Cancer Therapy. Onco. 2024; 4(3):217-231. https://doi.org/10.3390/onco4030016

Chicago/Turabian Style

Wang, Yina, and Liangyou Rui. 2024. "Targeting the Hippo- Yes-Associated Protein/Transcriptional Coactivator with PDZ-Binding Motif Signaling Pathway in Primary Liver Cancer Therapy" Onco 4, no. 3: 217-231. https://doi.org/10.3390/onco4030016

Article Metrics

Back to TopTop