https://doi.org/10.5812/pmco-124241

Hippo Signaling Pathway and Cancer: Molecular Regulation and Therapeutic Targets

authors:

avatar Fariba Dehghanian ORCID 1 , * , avatar Seyedeh Zahra Hosseini Imani ORCID 1 , avatar Amirhosein Naghsh-Nilchi ORCID 1 , avatar Sheyda Khalilian ORCID 1

Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, 81746-73441, Isfahan, Iran
Precision Medicine and Clinical OMICS: Vol.2, issue 1; e124241
published online: July 11, 2022
article type: Review Article
received: March 23, 2022
revised: April 25, 2022
accepted: April 26, 2022

how to cite: Dehghanian F, Hosseini Imani S Z, Naghsh-Nilchi A, Khalilian S. Hippo Signaling Pathway and Cancer: Molecular Regulation and Therapeutic Targets. Artif Intell Precis Med. 2022;2(1):e124241. https://doi.org/10.5812/pmco-124241.

Abstract

The Hippo signaling pathway is one of the critical regulators of organ growth and proliferation. This pathway was first described in Drosophila, and now it is identified as one of the most conserved molecular pathways in all multicellular organisms. Recent studies have shown that the dysregulation of the Hippo pathway is associated with various cancers, contributing to tumorigenesis and cancer progression. Numerous attempts have been made to target the major components of this pathway for therapeutic interventions. YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ binding motif) molecules are the critical components involved in the Hippo pathway. These factors have been identified as essential in the incidence and progression of cancer and drug resistance. The intracellular localization of YAP/TAZ is a crucial regulator of its activity, i.e., activating the transcription of their target genes and, eventually, the possible development of cancer. The abundance of YAP/TAZ in the nucleus has been observed in many human cancers. Therefore, recent research has investigated direct and indirect therapeutic approaches to inhibit this localization. This study describes the Hippo signaling pathway, its components, molecular regulation, and involvement in cancer development. Finally, we examine new therapeutic targets aimed at regulating this pathway.

1. Context

Regulation of the cell number plays a vital role in tissue growth and homeostasis, and its dysregulation leads to tumorigenesis or organ degradation (1, 2). It has been shown that the Hippo signaling pathway (also known as Salvador-Warts-Hippo) plays a vital role in these processes (3). In Drosophila and vertebrates, the cell number modulates cell proliferation processes, cell death, and cell differentiation (4). During growth and development, cell proliferation is necessary for expanding the size of the organs and the body. In addition, the proper cell differentiation ensures the proper function of organ growth. Aged or damaged cells go through cell death, and adult stem cells divide and differentiate to replace them (5, 6). Under pathological conditions such as injuries and organ repair, cell division and differentiation of tissue-specific progenitor cells are increased to compensate for lost cells (7). On the other hand, uncontrolled cell proliferation and reduced cell death lead to tumorigenesis (8-10). The detailed mechanisms associated with cell proliferation, cell death, and cell differentiation have been widely studied. However, it is not yet completely understood how these processes are regulated (Figure 1).

Demonstration of the Hippo pathway in cell biology. The Hippo pathway responds to diverse stimuli, such as G-protein-coupled receptor signaling, nutrient, and metabolism, cell-cell or cell-matrix contact, mechanic cues, actin cytoskeleton, and various stress signals. Based on the stimuli, the Hippo pathway controls different biological processes, including cell proliferation, organ size, and cell survival. The Hippo pathway also plays a crucial role in tumorigenesis, differentiation, organ development, and homeostasis.
Demonstration of the Hippo pathway in cell biology. The Hippo pathway responds to diverse stimuli, such as G-protein-coupled receptor signaling, nutrient, and metabolism, cell-cell or cell-matrix contact, mechanic cues, actin cytoskeleton, and various stress signals. Based on the stimuli, the Hippo pathway controls different biological processes, including cell proliferation, organ size, and cell survival. The Hippo pathway also plays a crucial role in tumorigenesis, differentiation, organ development, and homeostasis.
Figure 1.

Demonstration of the Hippo pathway in cell biology. The Hippo pathway responds to diverse stimuli, such as G-protein-coupled receptor signaling, nutrient, and metabolism, cell-cell or cell-matrix contact, mechanic cues, actin cytoskeleton, and various stress signals. Based on the stimuli, the Hippo pathway controls different biological processes, including cell proliferation, organ size, and cell survival. The Hippo pathway also plays a crucial role in tumorigenesis, differentiation, organ development, and homeostasis.

The Hippo pathway modulates cell proliferation, differentiation, and death processes. The Hippo pathway's regulation of many cellular processes indicates the essential role of this pathway in various physiological and pathological conditions, such as growth, evolution, tissue homeostasis, and tumorigenesis (5). The Hippo pathway has a unique capacity for tumor formation and progression. Mutations and dysregulated expression of its main components (MST1/2, LATS1/2, YAP, TAZ) can cause cancer cells' migration, invasion, and malignancy. The biological importance of this pathway in tumorigenesis has received much attention in the last few years. Therefore, in this review study, we examine the function of different components of the Hippo signaling pathway, its molecular regulation, and its involvement in tumorigenesis and cancer progression. Finally, we will investigate the role of this pathway in cancer treatment.

2. Evidence Acquisition

2.1. Hippo Signaling Pathway

Recently, the Hippo pathway has been identified as a pathway that induces cell differentiation and death and prevents cell proliferation. Therefore, the Hippo pathway can be introduced as a critical pathway in coordinating these biological processes (11). In addition, this pathway has a role in tissue growth control, cell fate determination, mitosis, and pluripotency (12). Dysfunction of the Hippo pathway has also been reported in many human cancers (13). The Hippo pathway was first identified in Drosophila and defined by demonstrating genetic mosaicity for tumor suppressor genes (14). Genetic inactivation of genes, including Warts (Wts), Hippo (Hpo), Salvador (Sav), and Mats, can develop similar phenotypes with increased tissue growth. Yorkie (Yki) is one of the critical downstream targets in the Hippo pathway that regulates transcription by interacting with the Scalloped (Sd) transcription factor (15). The Hippo pathway is highly conserved among mammals. Alteration of its activity leads to significant changes in the size of organs, especially the liver (16). Macrophage stimulating 1/2 (Mst1/2) (ortholog Hpo), large tumor suppressor 1/2 (Lats1/2) (ortholog Wts), Sav1, and MPSON binder 1 (Mob1) (ortholog Mobkl1A, Mobkl1B, Mobkl1C) construct a kinase cascade that phosphorylates and inhibits Yes-associated protein 1/Tafazzin (YAP/TAZ) (ortholog Yki) upon activation. YAP/TAZ performs essential physiological functions in the Hippo pathway through binding to transcriptional enhancer factor (TEF) and ABAA domain (Tead 1-4) (Sd orthologs) (Figure 2). The core members of the Hippo-pathway are well-identified in Drosophila and mammals, but this pathway's regulatory mechanisms have been rarely studied (17, 18).

The central core of the Hippo pathway. Macrophage stimulating 1/2 (Mst1/2) leads to the phosphorylation of Sav, large tumor suppressor 1/2 (Lats1/2), MPSON binder 1 (Mob1), and Lats1/2 phosphorylate Yes-associated protein 1/Tafazzin (YAP/TAZ). Subsequently, phosphorylated YAP/TAZ interacts with 14-3-3, resulting in the retention and degradation of YAP/TAZ in the cytoplasm. Without nuclear Yap, the expression of transcriptional enhancer factor (TEF) and ABAA domain (Tead) target genes is suppressed. In contrast, when YAP/TAZ is dephosphorylated (the Hippo signaling is inactive), they enter the nucleus and control the expression of a group of genes by interacting with Tead1-4 and activating the transcription of target genes.
The central core of the Hippo pathway. Macrophage stimulating 1/2 (Mst1/2) leads to the phosphorylation of Sav, large tumor suppressor 1/2 (Lats1/2), MPSON binder 1 (Mob1), and Lats1/2 phosphorylate Yes-associated protein 1/Tafazzin (YAP/TAZ). Subsequently, phosphorylated YAP/TAZ interacts with 14-3-3, resulting in the retention and degradation of YAP/TAZ in the cytoplasm. Without nuclear Yap, the expression of transcriptional enhancer factor (TEF) and ABAA domain (Tead) target genes is suppressed. In contrast, when YAP/TAZ is dephosphorylated (the Hippo signaling is inactive), they enter the nucleus and control the expression of a group of genes by interacting with Tead1-4 and activating the transcription of target genes.
Figure 2.

The central core of the Hippo pathway. Macrophage stimulating 1/2 (Mst1/2) leads to the phosphorylation of Sav, large tumor suppressor 1/2 (Lats1/2), MPSON binder 1 (Mob1), and Lats1/2 phosphorylate Yes-associated protein 1/Tafazzin (YAP/TAZ). Subsequently, phosphorylated YAP/TAZ interacts with 14-3-3, resulting in the retention and degradation of YAP/TAZ in the cytoplasm. Without nuclear Yap, the expression of transcriptional enhancer factor (TEF) and ABAA domain (Tead) target genes is suppressed. In contrast, when YAP/TAZ is dephosphorylated (the Hippo signaling is inactive), they enter the nucleus and control the expression of a group of genes by interacting with Tead1-4 and activating the transcription of target genes.

Mst1/2 are protein kinases of the sterile 20 (STE20) family that phosphorylate Sav, Lats1/2, and Mob1. Mst1/2 kinetic activity is enhanced by interacting with Sav, mediated by SARAH domains in Mst1/2 and Sav (19). In addition, thousand and one (TAO) or TAOK1-3 kinase has been shown to phosphorylate and activate Mst1/2 or Hpo directly (20). In Drosophila, Ras-assocaition family (RASSF) competes with Sav and leads to dephosphorylation and inactivation of Mst1/2 by adsorption of the protein phosphatase 2A (PP2A) complex. Mst1/2 directly phosphorylates and activates Lats1/2. Sav1 acts as a bridge to bring Mst1/2 and Lats1/2 together (21). There is also some evidence that MST1/2 are activated without upstream kinases. They are only activated by autophosphorylation of MST1/2. Another critical component called NF2/Merlin facilitates Lats1/2 phosphorylation by the MST1/2-Sav complex. When Mst1/2 is active, there are two groups of MAP4Ks called MAP4K1/2/3/5 (Hppy ortholog) and MAP4K4/6/7 (Msn ortholog) that directly phosphorylate LATS1/2 (6, 22).

Lats1/2 phosphorylates YAP/TAZ directly. When YAP/TAZ is phosphorylated, it remains in the cytoplasm due to its interaction with the protein 14-3-3. Therefore, the transcription of its target genes is inhibited. Whereas, when upstream kinases are inactivated, dephosphorylated YAP/TAZ enter the nucleus and regulate gene expression. YAP/TAZ phosphorylation also regulates their protein stability (23). Recently, several proteins have been discovered that directly regulate YAP displacement and activation without Lats (5). YAP/TAZ does not have a DNA-binding domain, so they bind to the promoter of target genes by interacting with DNA-binding transcription factors. YAP/TAZ primarily binds to TEAD1-4 transcription factors and control genes involved in cell proliferation and death (5). TEAD1-4 can bind to VGLL4 in the nucleus and act as a transcriptional suppressor. The interaction between YAP/TAZ and TEAD1-4 causes the separation of VGLL4. Also, TEAD-mediated activation induces tissue growth and inhibits apoptosis (24). In addition to TEADs, YAP/TAZ interacts with other transcription factors, such as Smad1, Smad2/3, Smad7, RUNX1/2, P63/P73, and ErbB4. It also controls the transcription of various genes involved in proliferation, differentiation, and growth (25) (Table 1).

Table 1.

Function of the Main Components of the Hippo Pathway

DrosophilaMammalsMain Function
Hippo (Hpo)Mst1/2Phosphorylation of Lats1/2 and Mob1 and Sav1
Salvador (Sav) Sav1Interaction with Mst1/2 and promotion of Lats phosphorylation
Warts (Wts)Lats1/2Phosphorylation and inactivation of YAP/TAZ
MatsMob1 A/BScaffold protein LATS1/2
Yorkie (Yki)YAP/TAZHelper for transcription activator (main pathway elements)
Scalloped (Sd) TEAD1-4Transcription factor
TgiVGLL4YAP/TAZ function inhibitor
MerlinMerlin/NF2Facilitate Lats activation by Mst1/2

2.2. Regulation of the Hippo Pathway in Physiological and Pathological Conditions

In recent years, the Hippo pathway has been shown to regulate stem cell function. YAP/TAZ is required to maintain pluripotency in mouse and human embryonic stem cells (26). Increased YAP/TAZ activity in transgenic mice promotes tissue-specific stem cell proliferation and blocks cell differentiation (17). YAP/TAZ is also necessary for the differentiation of mesenchymal stem cells. Silencing YAP/TAZ in these cells reduces osteogenesis and increases lipid production (27). In addition, many studies have suggested the role of YAP/TAZ in the differentiation of muscle cells (28). These results indicate that the Hippo pathway plays an essential role in cell differentiation. The Hippo pathway is also involved in tissue repair (29). In the mouse intestine, the amount of YAP protein is significantly increased due to injuries, which promotes the regeneration and repair of the epithelium of the damaged intestine. However, YAP inactivation intensely leads to incomplete repair and reconstruction (30). YAP plays a vital role in early embryonic development. In mice, YAP silencing is lethal as it stops fetal growth on day 8.5. This leads to abnormalities in the yolk sac, angiogenesis, and elongation of the body axis (31). The Hippo pathway is known as the signaling pathway controlling the organ size. In Drosophila, the loss of function mutations in Hpo, Sav, Wts, and Mob results in significant tissue growth, as shown by large eyes and wings (5). Increased Yki expression also shows a similar increase in tissue growth (32). In mammals, the Hippo pathway function is protected to control the organ size. For example, increased expression of YAP, specifically in rat liver and heart tissue, results in a significant increase in both organs.

In addition, the silencing of Mst1/2 and Sav in the liver and heart leads to an increase in size (33). Parts of this pathway have been identified as tumor suppressors in Drosophila. The kinases present in the pathway are usually tumor suppressors. On the other hand, YAP/TAZ has a proto-oncogenic function (34). Increased expression of YAP/TAZ has been widely found in human cancers (35). Transgenic mice overexpressing YAP also obtain tumors and hyperplasia (36). Similarly, inactivation of major and upstream members of the Hippo pathway leads to tumor metastasis in mice (37, 38). In addition, NF2 inactivation, a tumor suppressor that acts upstream of the Hippo pathway, leads to increased tissue growth in Drosophila and cancer in mice (39, 40) (Figure 3).

Yes-associated protein 1/Tafazzin (YAP/TAZ) activity in different conditions. YAP/TAZ activity can affect stem cells and embryo development, organ size, and tumorigenesis. The Hippo pathway can modulate its effects on tissue size, cancer, and organ development by directly regulating stem cells (ESC, MSC, CSC, progenitors) proliferation and maintenance.
Yes-associated protein 1/Tafazzin (YAP/TAZ) activity in different conditions. YAP/TAZ activity can affect stem cells and embryo development, organ size, and tumorigenesis. The Hippo pathway can modulate its effects on tissue size, cancer, and organ development by directly regulating stem cells (ESC, MSC, CSC, progenitors) proliferation and maintenance.
Figure 3.

Yes-associated protein 1/Tafazzin (YAP/TAZ) activity in different conditions. YAP/TAZ activity can affect stem cells and embryo development, organ size, and tumorigenesis. The Hippo pathway can modulate its effects on tissue size, cancer, and organ development by directly regulating stem cells (ESC, MSC, CSC, progenitors) proliferation and maintenance.

Recent studies have investigated YAP's role in the progression of cancer metastasis in mice and TAZ in maintaining the self-renewal of breast cancer stem cells (41). This information indicates the critical role of the Hippo pathway in cancer metastasis (42, 43). The correlation between the Hippo pathway, mechanical stress, and the G protein-coupled receptor (GPCR) signaling pathway has also provided a new perspective on cancer metastasis. GPCRs are cell membrane proteins that attach to their ligands outside the cell and transmit signals from these materials to an intracellular molecule called G protein. Cells may form wider local adhesions to the extracellular matrix following the loss of cell-cell junctions and loss of cellular polarity. As a result, they are more likely to stimulate GPCR ligands (5, 44). Under such conditions, YAP/TAZ activation facilitates cell proliferation and migration. GPCRs are vital factors in cancer promotion whose dysregulation has been identified in various human cancers. GPCR signaling has several roles in cancer development (45) (Figure 4). Overall, the activation of YAP/TAZ through dysregulated GPCR signaling plays an essential role in promoting cancers (46).

Hippo pathway and GPCR signaling. Yes-associated protein 1/Tafazzin (YAP/TAZ) activity is controlled by cell density, extracellular matrix, and GPCR signaling. Elimination of cell junctions induces mechanical stress, leading to changes in cell morphology and YAP/TAZ localization in the nucleus. Through the activation of G proteins and possibly rearrangements of the actin cytoskeleton, G protein-coupled receptor (GPCR) signaling can potently modulate the phosphorylation states and activity of YAP/TAZ. Ectopic GPCR signaling can activate YAP/TAZ. High expression of GPCR or Gα-activating mutations may cause YAP/TAZ nuclear localization, leading to cancer proliferation.
Hippo pathway and GPCR signaling. Yes-associated protein 1/Tafazzin (YAP/TAZ) activity is controlled by cell density, extracellular matrix, and GPCR signaling. Elimination of cell junctions induces mechanical stress, leading to changes in cell morphology and YAP/TAZ localization in the nucleus. Through the activation of G proteins and possibly rearrangements of the actin cytoskeleton, G protein-coupled receptor (GPCR) signaling can potently modulate the phosphorylation states and activity of YAP/TAZ. Ectopic GPCR signaling can activate YAP/TAZ. High expression of GPCR or Gα-activating mutations may cause YAP/TAZ nuclear localization, leading to cancer proliferation.
Figure 4.

Hippo pathway and GPCR signaling. Yes-associated protein 1/Tafazzin (YAP/TAZ) activity is controlled by cell density, extracellular matrix, and GPCR signaling. Elimination of cell junctions induces mechanical stress, leading to changes in cell morphology and YAP/TAZ localization in the nucleus. Through the activation of G proteins and possibly rearrangements of the actin cytoskeleton, G protein-coupled receptor (GPCR) signaling can potently modulate the phosphorylation states and activity of YAP/TAZ. Ectopic GPCR signaling can activate YAP/TAZ. High expression of GPCR or Gα-activating mutations may cause YAP/TAZ nuclear localization, leading to cancer proliferation.

2.3. Hippo Signaling Pathway in Cancer

The Hippo signaling pathway regulates many tumorigenic processes (47). The Hippo pathway regulates many cellular features associated with tumorigenesis. This pathway is regulated by cellular properties such as cellular polarity, cell-cell adhesion, contact inhibition process, and mechanical cues. On the other hand, it controls cell proliferation, cell survival, maintaining stem cell characteristics, metastasis, cell recovery, and regeneration (42). Disorders in the Hippo pathway have been reported frequently in many human carcinomas, including lung, colorectal, ovarian, liver, and prostate cancers (48). Some Hippo pathway members have been identified as tumor suppressor genes reduced in cancer (49). Other parts have been reported as oncogenes increasing in cancer (30, 50, 51). Also, the core members of this pathway, including YAP/TAZ activators and Tead1-4 transcription factors, have been reported as oncogenes. Two general mechanisms are involved in the dysregulation of the Hippo pathway, including changes in the expression and mutations of pathway members and Hippo pathological disorders associated with other signaling pathways (20, 52). Today, this pathway is also considered a therapeutic target in cancer (53). Since the Hippo kinase pathways and YAP are key pathway activators, they can apply for primary therapeutic purposes. Usually, kinases are considered the best targets for treatment with macromolecules (54).

2.4. Hippo Pathway and Cancer Treatment

Any changes in the YAP/TAZ level in the nucleus can cause a variation in the transcription of the target genes (35). High levels of dephosphorylated YAP/TAZ proteins are present in active and dividing cells or cancer cells, increasing the cell's primary activities, including cell proliferation and tumorigenesis (55). According to the proposed classical model, the YAP/TAZ cytoplasmic-nuclear exchanges are not binary but react to a continuous spectrum of cytoplasmic-nuclear currents (35). In the nucleus, excessive YAP/TAZ with increased TEAD expression increases drug resistance in most cancers, including breast, gastric, urinary, genital tract, female reproductive organs, skin, bone, and brain cancers (56, 57).

On the other hand, disruption and especially the lack of upstream tumor inhibitors in the Hippo pathway activate YAP in the nucleus, which, in turn, activates tumorigenic promoters (58). Therefore, YAP/TAZ nuclear localization inhibition can be used as a therapeutic method (35). Drugs that indirectly prevent YAP/TAZ from accumulating in the nucleus can suppress the transcriptional signaling pathway activating the target genes (59). For example, Dasatinib, Statins, and Pazopanib are drugs that block the YAP/TAZ nuclear localization in breast cancer cells (60). There are key potentially therapeutic sites in protein-protein interactions between YAP/TAZ and TEAD (55).

The wound-healing process in injured tissue is accompanied by the release of cytokines and transcription factors that activate and differentiate fibroblasts from myofibroblasts. Myofibroblasts are responsible for fibrogenesis and the production of Extracellular Matrix (ECM) components such as collagen, laminin, and fibronectin (61). In the case of chronic injury associated with prolonged inflammation, myofibroblasts' intensity increases ECM production, resulting in fibrosis. Also, myoblasts are the primary keys to promoting fibrosis, metastasis, invasion, and tumor formation under stressful conditions. It has recently been shown that the Hippo pathway is involved in fibrosis and tumorigenesis due to ECM changes by myofibroblasts (62). Recent findings indicate that YAP/TAZ and ECM work together to increase matrix strength, thus increasing YAP/TAZ oncogenic activity (63). YAP/TAZ induces cell differentiation of fibroblasts into myofibroblasts. They can also cause fibrosis in almost all vital organs such as the lungs, kidneys, liver, heart, and skin by different mechanisms. The activation of YAP/TAZ in response to matrix stiffness also causes tumorigenesis. Increased ECM stiffness increases YAP cellular activity, leading to the expression of its target genes. Therefore, inhibitory drugs that target the Hippo pathway can help treat both fibrosis and cancer. In the following, we will review the articles published in recent years and introduce and describe the mechanisms of drugs that target different components of the Hippo pathway, especially YAP/TAZ (64).

2.5. Hippo Pathway as Therapeutic Targets

Decursin is a compound isolated from the Dang-Gui plant's roots, which has recently been shown to have anti-cancer therapeutic uses. Decursin enables the inhibition of YAP activity in liver cancer cells (65). Cucurbitacins are tetracyclic compounds derived from several plant families, such as Cruciferae and Cucurbitaceae. These compounds have various medicinal activities, including antioxidant, anti-cancer, and anti-diabetic functions. Chai et al. reported the anti-cancer activity of Cucurbitacin B in colorectal cancer cells by inhibiting YAP protein (66).

Verteporfin is a small molecule that inhibits the interaction between YAP and TEAD, thereby suppressing YAP function (67, 68). Several researchers have found that Verteporfin can hinder the growth of cancer cells in some tumors, such as retinoblastoma and ovarian cancer. In addition to Verteporfin, other members of the porphyrin family, such as hematoporphyrin and protoporphyrin IX, are currently known to disrupt the YAP-TEAD interaction in mouse models. These can be considered the future candidates for cancer treatment (69). Dimethyl fumarate also significantly inhibits the nuclear localization of YAP in skin fibroblasts of patients with systemic sclerosis, thus preventing the development of dermal fibrosis (55, 70). According to recent studies, due to the relationship between the cytoskeleton and the intracellular localization of YAP/TAZ, cytoskeletal-modifying drugs can be used to target YAP and TAZ (71). For example, the inhibition of Rho-kinase has been shown to reduce the localization of YAP/TAZ, thereby reducing tumorigenesis (72). In addition, experiments have shown that the members of the Hippo pathway can be involved in drug resistance. For example, increased YAP/TAZ expression and dephosphorylation induce taxol resistance in several cancer types (58, 73).

About two decades ago, the Hippo pathway was identified when studying tissue growth in Drosophila. Then, it was widely studied in mammals. The regulation of the Hippo pathway is essential, as it controls tissue growth, mitosis, cell pluripotency, cell proliferation, differentiation, survival, growth, migration, death, and organ size. The core members of the Hippo pathway control the expression of a group of genes by phosphorylating and dephosphorylating YAP/TAZ. The Hippo pathway can affect cell carcinogenesis through different mechanisms. Also, these factors can make cancer cells resistant to existing therapies. Therefore, researchers are trying to find new therapeutic drugs targeting the Hippo pathway directly or indirectly. Computer modeling identified a unique compound called CPD3.1, which disrupted YAP interaction with TEADs. It also suppressed TEAD transcriptional activity, cell proliferation, and cell migration (74).

Similarly, MYF-01-37 has recently been identified to disrupt TEADs-YAP/TAZ binding by covalent binding to TEADs. According to studies, treatment of patients with MYF-01-37, combined with EGFR and MEK inhibitors, will target EGFR-mutated lung cancer cells (75).

Vestigial-like protein family members (VGLL1 – VGLL4) factors interact with TEADs through their Tondu domains (TDUs) and are considered TEAD transcription activators. VGLL4 is also known to be a tumor suppressor that reduces the formation of gastric cancer. Mechanically, VGLL4 competes with YAP to bind to TEADs via the TDU domain and thus acts as a YAP antagonist. However, the mechanical details of how VGLL4 is regulated in cancer are unclear (76). Despite much research about the Hippo signaling pathway, there are still ambiguities in choosing the best, most effective, and safest treatment approaches. Therefore, further studies are needed to discover mechanisms or molecules that regulate YAP/TAZ activity to provide promising therapeutic purposes in cancer progression.

Acknowledgements

References

  • 1.

    Motovali-Bashi M, Biglari M, Rezaei H, Dehghanian F. CYP1B1 L432V polymorphism and lung cancer risk in the Iranian population. Iran J Biotechnol. 2013;11(3):199-204.

  • 2.

    Motovali-Bashi M, Rezaei H, Dehghanian F, Rezaei H. Association between XPD (Lys751G1n) Polymorphism and Lung Cancer Risk: A Population-Based Study in Iran. Cell J. 2014;16(3):309-14. [PubMed ID: 24611140]. [PubMed Central ID: PMC4204198].

  • 3.

    Ding R, Berger C. Hippo pathway regulates neural stem cell quiescence. Cell Cycle. 2016;15(12):1525-6. [PubMed ID: 27058021]. [PubMed Central ID: PMC4934065]. https://doi.org/10.1080/15384101.2016.1171653.

  • 4.

    Sun SG, Wu S, Zhang L. The discovery and expansion of Hippo signaling pathway in Drosophila model. Yi Chuan. 2017;39(7):537-45. [PubMed ID: 28757469]. https://doi.org/10.16288/j.yczz.17-051.

  • 5.

    Yu FX, Guan KL. The Hippo pathway: regulators and regulations. Genes Dev. 2013;27(4):355-71. [PubMed ID: 23431053]. [PubMed Central ID: PMC3589553]. https://doi.org/10.1101/gad.210773.112.

  • 6.

    Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev. 2016;30(1):1-17. [PubMed ID: 26728553]. [PubMed Central ID: PMC4701972]. https://doi.org/10.1101/gad.274027.115.

  • 7.

    Losick VP. Wound-Induced Polyploidy Is Required for Tissue Repair. Adv Wound Care (New Rochelle). 2016;5(6):271-8. [PubMed ID: 27274437]. [PubMed Central ID: PMC4876532]. https://doi.org/10.1089/wound.2014.0545.

  • 8.

    Dehghanian F, Kay M, Vallian S. F1174V mutation alters the ALK active conformation in response to Crizotinib in NSCLC: Insight from molecular simulations. J Mol Graph Model. 2017;75:287-93. [PubMed ID: 28622610]. https://doi.org/10.1016/j.jmgm.2017.06.010.

  • 9.

    Kay M, Dehghanian F. Exploring the crizotinib resistance mechanism of NSCLC with the L1196M mutation using molecular dynamics simulation. J Mol Model. 2017;23(11):323. [PubMed ID: 29067524]. https://doi.org/10.1007/s00894-017-3495-5.

  • 10.

    Wang X, Xia Y. microRNA-328 inhibits cervical cancer cell proliferation and tumorigenesis by targeting TCF7L2. Biochem Biophys Res Commun. 2016;475(2):169-75. [PubMed ID: 27181358]. https://doi.org/10.1016/j.bbrc.2016.05.066.

  • 11.

    Dehghanian F, Hojati Z, Hosseinkhan N, Mousavian Z, Masoudi-Nejad A. Reconstruction of the genome-scale co-expression network for the Hippo signaling pathway in colorectal cancer. Comput Biol Med. 2018;99:76-84. [PubMed ID: 29890510]. https://doi.org/10.1016/j.compbiomed.2018.05.023.

  • 12.

    Gregorieff A, Wrana JL. Hippo signalling in intestinal regeneration and cancer. Curr Opin Cell Biol. 2017;48:17-25. [PubMed ID: 28527754]. https://doi.org/10.1016/j.ceb.2017.04.005.

  • 13.

    Saucedo LJ, Edgar BA. Filling out the Hippo pathway. Nat Rev Mol Cell Biol. 2007;8(8):613-21. [PubMed ID: 17622252]. https://doi.org/10.1038/nrm2221.

  • 14.

    Atkins M. Drosophila Genetics: The Power of Genetic Mosaic Approaches. In: Hergovich A, editor. The Hippo Pathway: Methods and protocols. New York, USA: Humana; 2019. p. 27-42. https://doi.org/10.1007/978-1-4939-8910-2_2.

  • 15.

    Snigdha K, Gangwani KS, Lapalikar GV, Singh A, Kango-Singh M. Hippo Signaling in Cancer: Lessons From Drosophila Models. Front Cell Dev Biol. 2019;7:85. [PubMed ID: 31231648]. [PubMed Central ID: PMC6558396]. https://doi.org/10.3389/fcell.2019.00085.

  • 16.

    Su W, Zhu S, Chen K, Yang H, Tian M, Fu Q, et al. Overexpressed WDR3 induces the activation of Hippo pathway by interacting with GATA4 in pancreatic cancer. J Exp Clin Cancer Res. 2021;40(1):88. [PubMed ID: 33648545]. [PubMed Central ID: PMC7923337]. https://doi.org/10.1186/s13046-021-01879-w.

  • 17.

    Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-56. [PubMed ID: 24825474]. [PubMed Central ID: PMC4197875]. https://doi.org/10.15252/embr.201438638.

  • 18.

    Fu V, Plouffe SW, Guan KL. The Hippo pathway in organ development, homeostasis, and regeneration. Curr Opin Cell Biol. 2017;49:99-107. [PubMed ID: 29316535]. [PubMed Central ID: PMC6348871]. https://doi.org/10.1016/j.ceb.2017.12.012.

  • 19.

    Han Y. Analysis of the role of the Hippo pathway in cancer. J Transl Med. 2019;17(1):116. [PubMed ID: 30961610]. [PubMed Central ID: PMC6454697]. https://doi.org/10.1186/s12967-019-1869-4.

  • 20.

    Plouffe SW, Meng Z, Lin KC, Lin B, Hong AW, Chun JV, et al. Characterization of Hippo Pathway Components by Gene Inactivation. Mol Cell. 2016;64(5):993-1008. [PubMed ID: 27912098]. [PubMed Central ID: PMC5137798]. https://doi.org/10.1016/j.molcel.2016.10.034.

  • 21.

    Yu FX, Zhao B, Guan KL. Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell. 2015;163(4):811-28. [PubMed ID: 26544935]. [PubMed Central ID: PMC4638384]. https://doi.org/10.1016/j.cell.2015.10.044.

  • 22.

    Morris ZS, McClatchey AI. Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma. Proc Natl Acad Sci U S A. 2009;106(24):9767-72. [PubMed ID: 19487675]. [PubMed Central ID: PMC2700996]. https://doi.org/10.1073/pnas.0902031106.

  • 23.

    Moon S, Kim W, Kim S, Kim Y, Song Y, Bilousov O, et al. Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization. EMBO Rep. 2017;18(1):61-71. [PubMed ID: 27979972]. [PubMed Central ID: PMC5210122]. https://doi.org/10.15252/embr.201642683.

  • 24.

    Pan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010;19(4):491-505. [PubMed ID: 20951342]. [PubMed Central ID: PMC3124840]. https://doi.org/10.1016/j.devcel.2010.09.011.

  • 25.

    Zhao B, Tumaneng K, Guan KL. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol. 2011;13(8):877-83. [PubMed ID: 21808241]. [PubMed Central ID: PMC3987945]. https://doi.org/10.1038/ncb2303.

  • 26.

    Han Z, Yu Y, Cai B, Xu Z, Bao Z, Zhang Y, et al. YAP/TEAD3 signal mediates cardiac lineage commitment of human-induced pluripotent stem cells. J Cell Physiol. 2020;235(3):2753-60. [PubMed ID: 31541452]. https://doi.org/10.1002/jcp.29179.

  • 27.

    Komatsu N, Kajiya M, Motoike S, Takewaki M, Horikoshi S, Iwata T, et al. Type I collagen deposition via osteoinduction ameliorates YAP/TAZ activity in 3D floating culture clumps of mesenchymal stem cell/extracellular matrix complexes. Stem Cell Res Ther. 2018;9(1):342. [PubMed ID: 30526677]. [PubMed Central ID: PMC6286508]. https://doi.org/10.1186/s13287-018-1085-9.

  • 28.

    Watt KI, Goodman CA, Hornberger TA, Gregorevic P. The Hippo Signaling Pathway in the Regulation of Skeletal Muscle Mass and Function. Exerc Sport Sci Rev. 2018;46(2):92-6. [PubMed ID: 29346163]. [PubMed Central ID: PMC6319272]. https://doi.org/10.1249/JES.0000000000000142.

  • 29.

    Wang Y, Yu A, Yu FX. The Hippo pathway in tissue homeostasis and regeneration. Protein Cell. 2017;8(5):349-59. [PubMed ID: 28130761]. [PubMed Central ID: PMC5413598]. https://doi.org/10.1007/s13238-017-0371-0.

  • 30.

    Hong AW, Meng Z, Guan KL. The Hippo pathway in intestinal regeneration and disease. Nat Rev Gastroenterol Hepatol. 2016;13(6):324-37. [PubMed ID: 27147489]. [PubMed Central ID: PMC5642988]. https://doi.org/10.1038/nrgastro.2016.59.

  • 31.

    Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24(9):862-74. [PubMed ID: 20439427]. [PubMed Central ID: PMC2861185]. https://doi.org/10.1101/gad.1909210.

  • 32.

    Gao Y, Zhang X, Xiao L, Zhai C, Yi T, Wang G, et al. Usp10 Modulates the Hippo Pathway by Deubiquitinating and Stabilizing the Transcriptional Coactivator Yorkie. Int J Mol Sci. 2019;20(23). [PubMed ID: 31795326]. [PubMed Central ID: PMC6928647]. https://doi.org/10.3390/ijms20236013.

  • 33.

    von Gise A, Lin Z, Schlegelmilch K, Honor LB, Pan GM, Buck JN, et al. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci U S A. 2012;109(7):2394-9. [PubMed ID: 22308401]. [PubMed Central ID: PMC3289361]. https://doi.org/10.1073/pnas.1116136109.

  • 34.

    Zhang X, Yang L, Szeto P, Abali GK, Zhang Y, Kulkarni A, et al. The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis. Oncogene. 2020;39(30):5267-81. [PubMed ID: 32561850]. https://doi.org/10.1038/s41388-020-1362-9.

  • 35.

    Shreberk-Shaked M, Oren M. New insights into YAP/TAZ nucleo-cytoplasmic shuttling: new cancer therapeutic opportunities? Mol Oncol. 2019;13(6):1335-41. [PubMed ID: 31050214]. [PubMed Central ID: PMC6547617]. https://doi.org/10.1002/1878-0261.12498.

  • 36.

    Zhang H, Pasolli HA, Fuchs E. Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc Natl Acad Sci U S A. 2011;108(6):2270-5. [PubMed ID: 21262812]. [PubMed Central ID: PMC3038759]. https://doi.org/10.1073/pnas.1019603108.

  • 37.

    Nishio M, Hamada K, Kawahara K, Sasaki M, Noguchi F, Chiba S, et al. Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice. J Clin Invest. 2012;122(12):4505-18. [PubMed ID: 23143302]. [PubMed Central ID: PMC3533542]. https://doi.org/10.1172/JCI63735.

  • 38.

    Patel SH, Camargo FD, Yimlamai D. Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis. Gastroenterology. 2017;152(3):533-45. [PubMed ID: 28003097]. [PubMed Central ID: PMC5285449]. https://doi.org/10.1053/j.gastro.2016.10.047.

  • 39.

    Zhang N, Bai H, David KK, Dong J, Zheng Y, Cai J, et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell. 2010;19(1):27-38. [PubMed ID: 20643348]. [PubMed Central ID: PMC2925178]. https://doi.org/10.1016/j.devcel.2010.06.015.

  • 40.

    Inaba M, Sorenson DR, Kortus M, Salzmann V, Yamashita YM. Merlin is required for coordinating proliferation of two stem cell lineages in the Drosophila testis. Sci Rep. 2017;7(1):2502. [PubMed ID: 28566755]. [PubMed Central ID: PMC5451480]. https://doi.org/10.1038/s41598-017-02768-z.

  • 41.

    Elaimy AL. The Convergence of VEGF-Neuropilin and YAP/TAZ Signaling Promotes Stem-Like Traits and DNA Repair in Breast Cancer [dissertation]. Massachusetts, USA: University of Massachusetts; 2019.

  • 42.

    Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246-57. [PubMed ID: 23467301]. https://doi.org/10.1038/nrc3458.

  • 43.

    Zeng Q, Hong W. The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. Cancer Cell. 2008;13(3):188-92. [PubMed ID: 18328423]. https://doi.org/10.1016/j.ccr.2008.02.011.

  • 44.

    Luo J, Yu FX. GPCR-Hippo Signaling in Cancer. Cells. 2019;8(5). [PubMed ID: 31072060]. [PubMed Central ID: PMC6563442]. https://doi.org/10.3390/cells8050426.

  • 45.

    Bagnato A, Rosano L. New Routes in GPCR/beta-Arrestin-Driven Signaling in Cancer Progression and Metastasis. Front Pharmacol. 2019;10:114. [PubMed ID: 30837880]. [PubMed Central ID: PMC6390811]. https://doi.org/10.3389/fphar.2019.00114.

  • 46.

    Liu AM, Wong KF, Jiang X, Qiao Y, Luk JM. Regulators of mammalian Hippo pathway in cancer. Biochim Biophys Acta. 2012;1826(2):357-64. [PubMed ID: 22683405]. https://doi.org/10.1016/j.bbcan.2012.05.006.

  • 47.

    Dehghanian F, Azhir Z, Akbari A, Hojati Z. New Insights into the Roles of Yes-Associated Protein (YAP1) in Colorectal Cancer Development and Progression. Ann Colorectal Res. 2019;7(2). https://doi.org/10.5812/acr.96458.

  • 48.

    Barron DA, Kagey JD. The role of the Hippo pathway in human disease and tumorigenesis. Clin Transl Med. 2014;3:25. [PubMed ID: 25097728]. [PubMed Central ID: PMC4112623]. https://doi.org/10.1186/2001-1326-3-25.

  • 49.

    Martin D, Degese MS, Vitale-Cross L, Iglesias-Bartolome R, Valera JLC, Wang Z, et al. Assembly and activation of the Hippo signalome by FAT1 tumor suppressor. Nat Commun. 2018;9(1):2372. [PubMed ID: 29985391]. [PubMed Central ID: PMC6037762]. https://doi.org/10.1038/s41467-018-04590-1.

  • 50.

    Chen Y, Han H, Seo G, Vargas R, Yang B, Chuc K, et al. The Hippo pathway origin and its oncogenic alteration in evolution. bioRxiv. 2019;Preprint. https://doi.org/10.1101/837500.

  • 51.

    Hong SH. Hippo pathway as another oncogenic mediator to promote immune evasion by PD-L1 signaling. J Thorac Dis. 2019;11(Suppl 3):S318-21. [PubMed ID: 30997208]. [PubMed Central ID: PMC6424728]. https://doi.org/10.21037/jtd.2019.01.16.

  • 52.

    Wei C, Wang Y, Li X. The role of Hippo signal pathway in breast cancer metastasis. Onco Targets Ther. 2018;11:2185-93. [PubMed ID: 29713187]. [PubMed Central ID: PMC5909795]. https://doi.org/10.2147/OTT.S157058.

  • 53.

    Konishi H, Kikuchi S, Ochiai T, Ikoma H, Kubota T, Ichikawa D, et al. Latrunculin a has a strong anticancer effect in a peritoneal dissemination model of human gastric cancer in mice. Anticancer Res. 2009;29(6):2091-7. [PubMed ID: 19528469].

  • 54.

    Ye S, Eisinger-Mathason TS. Targeting the Hippo pathway: Clinical implications and therapeutics. Pharmacol Res. 2016;103:270-8. [PubMed ID: 26678601]. https://doi.org/10.1016/j.phrs.2015.11.025.

  • 55.

    Kim CL, Choi SH, Mo JS. Role of the Hippo Pathway in Fibrosis and Cancer. Cells. 2019;8(5). [PubMed ID: 31100975]. [PubMed Central ID: PMC6562634]. https://doi.org/10.3390/cells8050468.

  • 56.

    Ghiso E, Migliore C, Ciciriello V, Morando E, Petrelli A, Corso S, et al. YAP-Dependent AXL Overexpression Mediates Resistance to EGFR Inhibitors in NSCLC. Neoplasia. 2017;19(12):1012-21. [PubMed ID: 29136529]. [PubMed Central ID: PMC5683041]. https://doi.org/10.1016/j.neo.2017.10.003.

  • 57.

    Ge L, Li DS, Chen F, Feng JD, Li B, Wang TJ. TAZ overexpression is associated with epithelial-mesenchymal transition in cisplatin-resistant gastric cancer cells. Int J Oncol. 2017;51(1):307-15. [PubMed ID: 28534974]. https://doi.org/10.3892/ijo.2017.3998.

  • 58.

    Calses PC, Crawford JJ, Lill JR, Dey A. Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities. Trends Cancer. 2019;5(5):297-307. [PubMed ID: 31174842]. https://doi.org/10.1016/j.trecan.2019.04.001.

  • 59.

    Nguyen CDK, Yi C. YAP/TAZ Signaling and Resistance to Cancer Therapy. Trends Cancer. 2019;5(5):283-96. [PubMed ID: 31174841]. [PubMed Central ID: PMC6557283]. https://doi.org/10.1016/j.trecan.2019.02.010.

  • 60.

    Oku Y, Nishiya N, Sugiyama S, Sato H, Uehara Y. Sensitisation of Cancer Cells to MLN8237, an Aurora-A Inhibitor, by YAP/TAZ Inactivation. Anticancer Res. 2018;38(6):3471-6. [PubMed ID: 29848699]. https://doi.org/10.21873/anticanres.12617.

  • 61.

    Xiao Y, Hill MC, Li L, Deshmukh V, Martin TJ, Wang J, et al. Hippo pathway deletion in adult resting cardiac fibroblasts initiates a cell state transition with spontaneous and self-sustaining fibrosis. Genes Dev. 2019;33(21-22):1491-505. [PubMed ID: 31558567]. [PubMed Central ID: PMC6824468]. https://doi.org/10.1101/gad.329763.119.

  • 62.

    Piersma B, Bank RA, Boersema M. Signaling in Fibrosis: TGF-beta, WNT, and YAP/TAZ Converge. Front Med (Lausanne). 2015;2:59. [PubMed ID: 26389119]. [PubMed Central ID: PMC4558529]. https://doi.org/10.3389/fmed.2015.00059.

  • 63.

    Otranto M, Sarrazy V, Bonte F, Hinz B, Gabbiani G, Desmouliere A. The role of the myofibroblast in tumor stroma remodeling. Cell Adh Migr. 2012;6(3):203-19. [PubMed ID: 22568985]. [PubMed Central ID: PMC3427235]. https://doi.org/10.4161/cam.20377.

  • 64.

    Dehghanian F, Hojati Z, Esmaeili F, Masoudi-Nejad A. Network-based expression analyses and experimental validations revealed high co-expression between Yap1 and stem cell markers compared to differentiated cells. Genomics. 2019;111(4):831-9. [PubMed ID: 29775782]. https://doi.org/10.1016/j.ygeno.2018.05.007.

  • 65.

    Li J, Wang H, Wang L, Tan R, Zhu M, Zhong X, et al. Decursin inhibits the growth of HepG2 hepatocellular carcinoma cells via Hippo/YAP signaling pathway. Phytother Res. 2018;32(12):2456-65. [PubMed ID: 30251417]. https://doi.org/10.1002/ptr.6184.

  • 66.

    Chai Y, Xiang K, Wu Y, Zhang T, Liu Y, Liu X, et al. Cucurbitacin B Inhibits the Hippo-YAP Signaling Pathway and Exerts Anticancer Activity in Colorectal Cancer Cells. Med Sci Monit. 2018;24:9251-8. [PubMed ID: 30566960]. [PubMed Central ID: PMC6320653]. https://doi.org/10.12659/MSM.911594.

  • 67.

    Gokey JJ, Sridharan A, Xu Y, Green J, Carraro G, Stripp BR, et al. Active epithelial Hippo signaling in idiopathic pulmonary fibrosis. JCI Insight. 2018;3(6). [PubMed ID: 29563341]. [PubMed Central ID: PMC5926907]. https://doi.org/10.1172/jci.insight.98738.

  • 68.

    Szeto SG, Narimatsu M, Lu M, He X, Sidiqi AM, Tolosa MF, et al. YAP/TAZ Are Mechanoregulators of TGF-beta-Smad Signaling and Renal Fibrogenesis. J Am Soc Nephrol. 2016;27(10):3117-28. [PubMed ID: 26961347]. [PubMed Central ID: PMC5042658]. https://doi.org/10.1681/ASN.2015050499.

  • 69.

    Wu L, Yang X. Targeting the Hippo pathway for breast cancer therapy. Cancers. 2018;10(11):422.

  • 70.

    Toyama T, Looney AP, Baker BM, Stawski L, Haines P, Simms R, et al. Therapeutic targeting of TAZ and YAP by dimethyl fumarate in systemic sclerosis fibrosis. J Invest Dermatol. 2018;138(1):78-88.

  • 71.

    Panciera T, Azzolin L, Cordenonsi M, Piccolo S. Mechanobiology of YAP and TAZ in physiology and disease. Nat Rev Mol Cell Biol. 2017;18(12):758-70.

  • 72.

    Meyer K, Morales‐Navarrete H, Seifert S, Wilsch‐Braeuninger M, Dahmen U, Tanaka EM, et al. Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration. Mol Syst Biol. 2020;16(2). e8985.

  • 73.

    Zhao Y, Yang X. Targeting the Hippo pathway to improve response to chemotherapy. In: Johnson DE, editor. Targeting Cell Survival Pathways to Enhance Response to Chemotherapy. Massachusetts, USA: Academic Press; 2019. p. 169-85.

  • 74.

    Smith SA, Sessions RB, Shoemark DK, Williams C, Ebrahimighaei R, McNeill MC, et al. Antiproliferative and Antimigratory Effects of a Novel YAP-TEAD Interaction Inhibitor Identified Using in Silico Molecular Docking. J Med Chem. 2019;62(3):1291-305. [PubMed ID: 30640473]. [PubMed Central ID: PMC6701825]. https://doi.org/10.1021/acs.jmedchem.8b01402.

  • 75.

    Kurppa KJ, Liu Y, To C, Zhang T, Fan M, Vajdi A, et al. Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway. Cancer Cell. 2020;37(1):104-122000000000000. [PubMed ID: 31935369]. [PubMed Central ID: PMC7146079]. https://doi.org/10.1016/j.ccell.2019.12.006.

  • 76.

    Deng X, Fang L. VGLL4 is a transcriptional cofactor acting as a novel tumor suppressor via interacting with TEADs. American journal of cancer research. 2018;8(6):932-43. [PubMed ID: 30034932].