Hippo signaling in cancer: regulatory mechanisms and therapeutic strategies
Zhao Huang
A , Yunhan Tan A B , Wei Zhang C D E , Xiangdong Tang F , Edouard C. Nice G * and Canhua Huang A *
A Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
B West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
C Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
D West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
E Medical Big Data Center, Sichuan University, Chengdu, 610041, China.
F Sleep Medicine Center, Department of Respiratory and Critical Care Medicine, Mental Health Center, Translational Neuroscience Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
G Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.
Zhao Huang is currently postdoctor in Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University. His research focuses on the tumor biology including the growth, metastasis and drug resistance of cancers. |
Yunhan Tan is currently an undergraduate student in West China School of Stomatology, Sichuan University. Her research focuses on the application of nanotechnology and immune therapy for head and neck squamous cell carcinomas. |
Prof. Wei Zhang graduated from the Clinical School of Medicine of West China University of Medical Sciences in 1985 and obtained a master’s degree in medicine in 1992. He has been working in West China Hospital since then. He is currently deputy secretary of the Party Committee of Sichuan University, the chief scientist of the Medical Big Data Center of Sichuan University and the director of the Biomedical Big Data Center of West China Hospital. He has successively undertaken over 20 projects including National 863 Program, National 973 Program, the 10th Five-Year Plan, the 11th Five-Year Plan, the 12th Five-Year Plan, the 13th Five-Year Plan, and National Natural Science Foundation projects. He has been awarded the First Prize of Natural Science by the Ministry of Education and the First Prize of Scientific and Technological Progress by Sichuan Province, among other awards. Under his leadership, the team has established a comprehensive biological database of depression and anxiety disorders in the Chinese population. His team is interested in providing a basis for early prevention, early diagnosis, and early personalized treatment of mental disorders. |
Prof. Xiangdong Tang is the chief physician of Mental Health Center, West China Hospital, Sichuan University. He has been engaged in the basic and clinical research of sleep disorders for a long time, and is good at the diagnosis and treatment of common sleep problems such as insomnia, dreaminess and rhythm disorder, as well as sleep disorders related to breathing. He is the academic and technical leader in Sichuan Province, vice chairman of the Sleep Medicine Expert Committee of the Chinese Medical Doctor Association, deputy director of the Sleep and Mental Health Professional Committee of the Chinese Sleep Research Association, and deputy director of the Sleep Disorders Professional Committee. He has been responsible for and participated in 7 scientific research projects, and has published over 100 SCI papers. |
Prof. Ed Nice obtained his Licentiate from the Royal Institute of Chemistry in London in Advanced Analytical Chemistry in 1972 and Fellowship of the Chemical Society London in 1973. He is currently Adjunct Professor at Monash University where he is Head of the Clinical Biomarker Discovery and Validation (Department of Biochemistry and Molecular Biology) and a scientific advisor to the Monash Antibody Technologies Facility (MATF), of which he was Director from 2009–2013. He holds a Visiting Professorship at Sichuan University s West China Hospital and an Adjunct position at Macquarie University. Ed s long-term research interests have been in biomarker discovery and validation, high throughput monoclonal antibody production and validation and clinical biomarker assay development, with a strong translational focus on colorectal cancer. |
Prof. Canhua Huang returned to China in 2005 and was appointed as a Professor of the State Key Lab of Biotherapy, West China Hospital, Sichuan University. In 2012, he won the National Science Fund for Distinguished Young Scholars of China, and took up the post of the Chief Scientist for National 973 Program entitled “Proteomics Profiling of the Redoxomes Associated with Virus-induced Carcinogenesis†from 2013 to 2017. In 2014, he was hired as the Changjiang Scholars Program Endowed Professor. In 2018, he served as the director of an Innovative Research Group of the National Nature Science Foundation of China, entitled “Redox Signaling Regulation and Carcinogenesisâ€. In 2020, he was a member of the 8th Discipline Evaluation Group of Academic Degrees Committee of The State Council (Basic Medicine Group). He was selected by Elsevier 2020 and 2021 China Highly Cited Scholar and won the First Prize of Natural Science Award of the Ministry of Education in 2020. |
Handling Editor: Mibel Aguilar
Australian Journal of Chemistry 76(8) 399-412 https://doi.org/10.1071/CH22241
Submitted: 21 November 2022 Accepted: 1 June 2023 Published: 7 July 2023
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)
Abstract
As an evolutionarily conserved pathway, Hippo signaling not only plays a key role in embryonic development, but also regulates the initiation and progression of cancer. The upstream factors regulating the Hippo pathway are complex, including cell–cell contact, cell–extracellular matrix contact, membrane receptor–ligand binding, and cytoskeletal tension. In response to these mechanical or soluble cues, the Hippo core kinases are activated or inactivated, regulating the activity of key transcription co-factor YAP/TAZ thus yielding biological consequences. In the context of neoplasm, dysregulation of Hippo signaling contributes to cancer hallmarks such as sustained proliferation, stem-like properties, and metastasis. Importantly, targeting Hippo signaling by chemicals is emerging as a promising anticancer strategy. This article briefly introduces the discovery process of the Hippo pathway, summarizes the upstream signals regulating the Hippo pathway, discusses the relationship between Hippo inactivation and cancer development, and highlights the potential use of chemicals targeting Hippo signaling in cancer treatment.
Keywords: cancer hallmarks, chemical inhibitors, embryonic development, Hippo signaling, oncogene, targeted therapy, tumor suppressor, YAP/TAZ.
Introduction
Tumor is a major threat worldwide, having a major impact on human health. However, further studies are urgently required to unravel the underlying biology. Scientists in different fields tend to interpret this problem from diverse perspectives, but fortunately these perspectives are highly interconnected. Thus, for example, geneticists usually explain the origin of tumors in terms of genetic mutations. However, in 1978, developmental biologist Beatrice Mintz pointed out that tumors arise from faulty developmental processes.[1] Similar to embryonic development, the tumorigenic ability of malignant cells is inhibited.[2] This evidence indicates that there is a tight correlation between embryonic development and tumorigenesis. Many hallmarks in cancer, such as cell proliferation, apoptosis, differentiation, and migration are also key features in embryonic or organ development, suggesting tumors are partly a problem in the field of developmental biology. Therefore, abnormal regulation of embryonic development-related pathways is an important cause of tumor initiation and progression. These signaling pathways include Wnt, Hedgehog, Notch, TGF-β, etc., which are highly conserved in evolution.[3–6] During embryonic development, these signaling pathways are activated and precisely regulated spatiotemporally. When the development process is completed, the corresponding pathways should revert to quiescence in order to keep the organs in their normal shape and size, which is the prerequisite for the organism to carry out its normal life function. In contrast, abnormal reactivation of these pathways in a well-developed organ often induces tumorigenesis, while underlying mechanisms are poorly understood.
Hippo is one of the key pathways in development, notably in organ size control.[7] Unlike other developmental pathways, activation of Hippo usually reflects the end of the developmental process, while inactivation of Hippo induces developmental and tumor-related phenotypes such as cell proliferation and migration. Therefore, Hippo is generally considered to be a tumor suppressive pathway.[8] The core of the Hippo pathway consists of a kinase cascade and downstream transcriptional/co-transcriptional factors. Briefly, when Hippo is activated, MST1/2 can be autophosphorylated or phosphorylated by TAO kinase; phosphorylated MST1/2 induce the phosphorylation of LATS1/2 by forming a complex with SAV1 and MOB1. Phosphorylated LATS1/2 further induce phosphorylation of the co-transcription factor YAP/TAZ, leading to the cytoplasmic retention or degradation of YAP/TAZ.[9] When the Hippo pathway is inhibited, the stability of the YAP/TAZ protein is enhanced, enabling YAP/TAZ translocation. YAP/TAZ is a well-known oncogene, which binds to transcription factor TEAD1–4 thus promoting tumorigenesis.[10] For example, clinicopathological analysis showed that inactivation of the Hippo signaling pathway was associated with poor prognosis in liver cancer patients.[11] Animal and cellular models also confirmed that the inactivation of the Hippo pathway can induce the initiation and progression of liver cancer both in vitro and in vivo.[12,13] In addition to liver cancer, the tumor suppressive role of Hippo signaling has been verified in a variety of tumors.[14]
The upstream signals controlling the Hippo pathway are extremely complex and can be roughly divided into mechanical factors and soluble signaling molecular factors. Specifically, it includes cell–cell contact, cell–extracellular matrix contact, membrane receptor–ligand binding, cytoskeleton tension, and liquid shear stress.[15–19] Under pathological conditions, these factors may be abnormally regulated, which inactivates the Hippo pathway, contributing to a series of tumor-related features such as aerobic glycolysis, persistent growth, metastasis, acquisition of tumor stem cell characteristics, and drug resistance.[20–23] In addition, the Hippo pathway can also interact with other signaling pathways (including the estrogen receptor, and IRS2/AKT and PI3K-TOR pathways) to form a complex signaling network, presenting a greater challenge for deciphering the cancer related mechanisms.[24–26]
Given the intrinsic link between the Hippo pathway and tumors, targeting the Hippo pathway is expected to be a promising anticancer strategy. Importantly, several chemical drugs have been shown to have potential therapeutic value by targeting components of the Hippo pathway. For example, verteporfin disrupts YAP–TEAD interactions and inhibits retinoblastoma.[27] This article will focus on the regulatory mechanisms of the Hippo pathway in the context of neoplasm, with a highlight on Hippo-targeting chemicals in order to provide new insights for cancer treatment.
A brief history of Hippo signaling
Organs maintain their normal size and shape in response to various stimuli, and this is an important prerequisite for their physiological functions. For example, it has long been found that in patients undergoing liver resection, the rest of the liver rapidly grows back to its original size and then automatically stops growing, indicating that organ size is finely regulated.[28] However, the molecular mechanisms continue to be unclear. In 1995, researchers found that homozygous deletion of the Warts gene in Drosophila resulted in tissue overgrowth and suggested that this event might contribute to tumor formation.[29] In 1999, researchers knocked out LATS1 (Warts homologous gene) in mice, and found that the knockout could form soft tissue sarcomas and ovarian cancer, confirming the tumor suppressive function of LATS1.[30] To date, as core components of the Hippo pathway, LATS1/2 have been extensively studied for their roles in tumor formation.[31] Other core components of the pathway, MST1/2, the mammalian ortholog of the Drosophila Hippo gene, were identified by multiple groups in 2003. These studies revealed that MST1/2 have similar functions to LATS1/2 in inhibiting tissue overgrowth.[32,33] In 2005, the downstream key effector YAP/TAZ (Yorkie in Drosophila) controlled by the Hippo pathway was discovered. Researchers have confirmed that LATS1/2 can phosphorylate YAP and induce the inactivation of YAP, thereby inhibiting cell proliferation, promoting apoptosis, and limiting tissue overgrowth, suggesting that YAP is an important oncogene.[34] However, YAP/TAZ lacks a DNA-binding domain, and thus, YAP/TAZ is more likely to function as a co-transcription factor rather than a transcription factor. In 2008, the YAP/TAZ interacting protein TEAD1–4 (Scalloped in Drosophila) was discovered, which binds directly to DNA and forms a transcriptional complex with YAP/TAZ, thus initiating transcriptional programs.[35,36] So far, the core of the Hippo pathway has only been partially discovered (Fig. 1).
A brief history of Hippo signaling. With increasing research, several key regulatory genes in the Hippo signaling pathway have been discovered (this figure does not include all components of the Hippo pathway). The corresponding genes between Drosophila and mammalian homologous are listed as follows: Wts-LATS1/2; Hpo-MST1/2; Yorkie-YAP/TAZ; Mats-MOB.
In addition, many other genes have also been identified as components of Hippo pathway, such as SAV and MOB, which can interact with LATS1 and mediate MST1/2-induced LATS1 phosphorylation.[37,38] Moreover, some factors regulating MST1/2 phosphorylation, such as RASSF1A and TAO-1, have also been found.[39,40] Additionally, MAP4K and STK25 have been shown to phosphorylate LATS1/2 independently of MST1/2.[41,42] Recently, focal adhesion kinase (FAK) was found to inhibit Hippo signaling by phosphorylating MOB1.[43] In addition, WWC1/2/3 were recently identified as novel Hippo regulators activating LATS1/2.[44] The discovery process behind these components has been comprehensively summarized elsewhere.[45] The regulatory factors of the Hippo pathway will continue to be established, allowing a more in-depth understanding of this pathway.
Upstream factors regulating Hippo signaling
To date, the Hippo pathway has been found to be regulated by a variety of upstream signals. These factors can be roughly divided into two categories, one is mechanical cues, such as the extrusion and stretching of cells, the stiffness of the extracellular matrix, and the liquid shear stress; the other is soluble cues, such as growth factor-receptor interactions (Fig. 2). Interestingly, it is worth noting that recent studies suggest Hippo signaling can also be regulated by heat, heavy metals, and glycogen accumulation.[46–48] Here, we summarize mechanical cues that can regulate Hippo signaling.
The upstream signals regulating Hippo signaling. Mechanical cues (including cell–cell contact, cell–extracellular matrix contact, cytoskeletal tension, and fluid shear stress) and soluble molecules (including certain hormones, growth factors, and chemokines) can regulate the activity of Hippo signaling.
Cell–cell contact
Contact inhibition is a common phenomenon in a monolayer cell culture, whereby when the cultured cells are at high confluence, cell–cell contact will inhibit their proliferation. This contact inhibition effect underlies the regulation of embryogenesis and cancer. During embryonic development, outer cells exhibit more pronounced YAP nuclear translocation due to a relatively low cell confluence, which contrasts to inner cells that are at high density.[49] In the context of neoplasm, cultured tumor cells frequently break contact inhibition and achieve a multi-layer or agglomerate growth. This suggests that under normal physiological conditions, the Hippo pathway can restrict cell proliferation by sensing cell–cell contact. In contrast, during tumorigenesis, the Hippo pathway is often inactivated and cell proliferation is therefore no longer restricted by contact inhibition. Since the cell membrane is the first contact site between cells, it is reasonable to assume that there should be certain sensors located on the cell membrane that transmit the contact signal into the cell, thereby regulating the Hippo pathway. In fact, many studies have shown that this cellular contact inhibitory signal is largely sensed by adhesion junction molecules on the cell membrane. One such well-known adhesion junction molecule is E-cadherin. At high confluence, E-cadherin on neighboring cell membranes forms a dimer, which activates Hippo signaling and inhibits cell proliferation.[50]
Similar to adhesion junctions, tight junctions also mediate cell–cell contact inhibition by regulating Hippo signaling. For example, the tight junction component Angiomotin can interact with the Hippo signaling component NF2 (also known as Merlin), both of which have been demonstrated to have tumor suppressive roles.[51] The following studies confirm that NF2 interacts with LATS1/2 thus activating the Hippo pathway, and that this interaction is dependent on the binding of NF2 to Angiomotin. Mutations in NF2, which disrupt the interaction with tight junctions, is involved in cancer development such as neurofibromas.[52]
Cell–extracellular matrix contact
Cells are not only in contact with neighboring cells, but also with the extracellular matrix (ECM). The ECM provides a place for cells to attach, and the signaling substances in it are also crucial for cell-to-cell communication. When the adherent cells detach from the ECM, most of them cannot survive in the circulation, which is called apoptosis or, more specifically, anoikis.[53] This effect profoundly determines the fate of cells during embryogenesis and tumorigenesis. For example, most terrestrial animals have webs between their fingers in the early embryonic stage. However, the webbed structure disappears via apoptosis during development.[54] Likewise, the disappearance of frogs tails during development is associated with apoptosis.[55] In the context of cancer, anoikis resistance is the prerequisite for the metastasis of tumor cells. Given the vital roles of the Hippo pathway during development, many researchers have speculated that the Hippo pathway may sense cell–ECM contact to regulate apoptosis or anoikis. Indeed, in non-cancerous cells, LATS1/2 are activated to inhibit YAP and induce apoptosis in response to cell detachment. During the malignant transformation of cells, inactivation of the Hippo pathway prevents anoikis.[16] In addition, more and more evidence shows that anoikis is an important line of defense against tumor metastasis, and anoikis resistance caused by Hippo pathway inactivation largely contributes to tumor metastasis.[56,57]
Further mechanistic studies have shown that the integrin family of proteins play critical roles in the connection between ECM and Hippo pathway. Integrins are important molecules that anchor cells to the ECM and are responsible for sensing signals from it.[58] It has been reported that integrins bind to fibrin and activate the focal adhesion kinase FAK, which in turn activates PI3K-PDK1 signaling, thereby regulating the Hippo pathway.[59,60] In addition, integrins can also inhibit NF2, a Hippo pathway regulator, by activating RAC and PAK1.[61] These studies have confirmed that cell–ECM contact is one of the upstream regulators of the Hippo pathway.
Cytoskeleton and mechanotransduction
Another key factor regulating the Hippo pathway is the remodeling of the cytoskeleton. It has long been observed that the cytoskeleton can regulate the function of YAP, but the mechanism was not elucidated.[62] Following studies suggest that filamentous actin (F-actin) may serve as a key regulator of the Hippo pathway. On the one hand, F-actin can interact with components of the Hippo pathway, such as LATS1 and AMOT, thereby regulating the Hippo pathway.[63,64] On the other hand, F-actin regulates the Hippo pathway by mechanotransduction, because the organization of F-actin reflects the state of intracellular tension. As mentioned above, cell–cell contact and cell–ECM contact also fall into the category of mechanical cues. Therefore, researchers often discuss the influence of mechanical cues on the Hippo pathway from two aspects, namely stretching force and extrusion force.[65] In Drosophila cells, F-actin overgrowth caused by gene mutation can activate YAP, leading to tissue hyperplasia.[66,67] In mammalian cells, stretching and compression of F-actin can activate and inhibit YAP, respectively.[68,69] Importantly, YAP can affect the ECM through its target genes, which in turn regulates the surrounding mechanical environment. For example, two major YAP target genes, CTGF and CYR61, mediate cellular responses to extracellular mechanical cues.[70,71] Moreover, it has been shown that RAP2 plays a key role in the mechanotransduction of the Hippo pathway.[19] Briefly, under low stiffness conditions, RAP2 is activated to interact with MAP4K and ARHGAP29, which activates LATS1/2 thus inhibiting YAP.[19]
In addition to these mechanical cues, there are some soluble cues that also regulate the Hippo pathway, such as G protein-coupled receptor signaling activated by certain hormones.[17] Intracellular metabolic changes can also have significant effects on the Hippo pathway.[72,73] The regulatory mechanisms of these factors on the Hippo pathway have been well summarized,[74] so they will not be discussed herein.
YAP/TAZ is key oncogene downstream of Hippo signaling
In most cases, Hippo inactivation-induced tumorigenesis is largely dependent on the activation of YAP/TAZ, which is a co-transcription factor with nucleocytoplasmic shuttling properties. When the Hippo pathway is activated, YAP/TAZ is phosphorylated and then retained in the cytoplasm or degraded by ubiquitination. When the Hippo pathway is inactivated, YAP/TAZ enters the nucleus and binds to TEAD1–4 to activate the transcription of target genes.[75] So far, high expression, low phosphorylation, nuclear translocation, and copy number amplification of YAP/TAZ have been found in a variety of tumors, suggesting that YAP/TAZ is an important oncogene.[65] For example, the nuclear expression of YAP/TAZ in tumors was correlated with poor prognosis in lung cancer patients.[76] Furthermore, the expression level of TAZ in triple-negative breast cancer, the most malignant breast cancer type, is significantly higher than that in other types of breast cancer.[77] In addition, YAP activation is associated with cetuximab resistance in colorectal cancer patients, thus resulting in a poor prognosis.[78] Moreover, the expression of YAP is higher in poorly differentiated liver cancer than in well differentiated liver cancer.[79] Apart from high expression, YAP is also activated by phase separation. In response to anti‐PD‐1 therapy, interferon‐γ (IFN‐γ) promotes phase separation of YAP in nucleus, where YAP forms transcriptional hubs with many other transcription factors/co‐factors to activate gene transcription, leading to tumor immunotherapy resistance.[80] In addition to the above cancer types, activation of YAP/TAZ has also been found in many other types of tumors (including gastric cancer, pancreatic cancer, glioma, melanoma, and ovarian cancer).[81] These findings suggest that YAP/TAZ, as an oncogene in general, is widely involved in the initiation and progression of tumors.
It is well known that tumors are largely caused by genetic mutations in driver genes, such as the gain of function of oncogenes and the loss of function of tumor suppressors. Recent studies have shown that YAP/TAZ also mediates the oncogenic roles of driver mutations. For instance, KRAS gene mutation drives various tumors, including lung and pancreatic cancer. In KRAS-mutated mouse models, researchers found that YAP is required for tumor formation.[82,83] In addition to KRAS, mutations in other key oncogenes or tumor suppressor genes (including APC and LKB1) have also been found to regulate the Hippo pathway.[10] In summary, YAP/TAZ plays an important role in tumorigenesis induced by Hippo pathway inactivation.
Inactivation of Hippo signaling induces various cancer hallmarks
The Hippo pathway involves multi-functional signaling, which not only regulates cell proliferation, but also affects cell migration, invasion, metabolism, and differentiation. Therefore, inactivation of the Hippo pathway may lead to multiple cancer hallmarks, including tumor growth, stemness, metastasis, and drug resistance (Fig. 3). Moreover, these features do not exist independently, but interact with each other. For example, metabolic reprogramming supports tumor growth by activating aerobic glycolysis.[84] Dedifferentiation of tumor cells elevates their stem-like characteristics, acquiring the ability for radio- and chemoresistance, and eventually leads to tumor metastasis.[85]
Inactivation of the Hippo signaling induces various cancer hallmarks. Since a majority of YAP target genes are oncogenes, inactivation of the Hippo pathway can induce a variety of cancer hallmarks such as rapid growth, stemness-like phenotype, or distant metastasis by promoting cell proliferation, dedifferentiation, and invasion.
Tumor growth
As mentioned previously, the Hippo pathway senses cell density. At high confluence, cell–cell contact activates the Hippo pathway and inhibits cell proliferation. When the Hippo pathway is inactivated, the proliferation of cells is no longer restricted, which may promote tumor formation. Using Drosophila as a model, researchers found that inactivation of the Hippo pathway induces the nuclear translocation of YAP, which promotes cell proliferation.[86] Similarly, YAP was found to induce organ overgrowth by promoting cell proliferation in mouse models.[87] In cellular models, knockdown of MST1/2, and activation of YAP or TEAD, can promote cell proliferation.[35,88,89] In addition, phase separation of glycogen can sequester MST1/2 in liquid droplets, abrogating their inhibitory function to YAP. This event increases YAP activity, resulting in tumorigenesis.[48] These data demonstrate that the Hippo pathway can finely regulate cell proliferation, suggesting an important role for this pathway in tumor growth.
Mechanistically, cell proliferation is often regulated by the cell cycle. The cell cycle can generally be divided into four phases, namely G1 phase (cell size enlargement), S phase (DNA replication), G2 phase (ready to divide), and M phase (division). Regulation of the cell cycle relies on the control of checkpoints, such as the G1/S checkpoint and the S/G2 checkpoint, which check for DNA damage before and after DNA replication, respectively. Cells with DNA damage may enter the DNA repair pathway or directly undergo apoptosis to avoid entering the S phase. However, dysregulation of the cell cycle may allow cells containing abnormal DNA to bypass the checkpoint and enter division, inducing tumor growth.[90]
Recent studies have revealed how inactivation of the Hippo pathway induces tumor cell proliferation by regulating the cell cycle.[21,91] In fact, it has been shown that YAP can facilitate cells to pass the G1/S and G2/M checkpoints.[92] For instance, in the resting state, the tumor suppressor gene (i.e. cell cycle arrest protein) RB interacts with E2F, inhibiting the function of E2F, thereby inducing cell cycle arrest at the G1/S checkpoint. During the progression of the cell cycle, the cyclin kinases CDK4 and CDK6 phosphorylate RB, leading to the dissociation of RB and E2F. This effect activates E2F function, thereby enabling cells to enter the S phase.[93] Importantly, YAP and TEAD can at least partially compensate for the function of E2F, and the E2F target gene c-Myc can be also transcriptionally activated by YAP.[94,95] This evidence suggests that even if the checkpoint proteins provide cell cycle arrest signals, inactivation of the Hippo pathway can bypass these restricting signals and allow cells to continue dividing.[96] In addition to c-Myc, many cell cycle-related proteins (including MCM3 and MCM6, etc.) are also transcriptionally activated by YAP.[97,98] These findings suggest that the Hippo pathway can also directly regulate cell cycle-related proteins, thereby promoting cell proliferation and tumor growth.
Cancer stemness
It has long been speculated that tumors are derived from a small subset of cells with self-renewal capacity, called cancer stem cells.[99] These cells often show strong DNA repair ability and drug resistance capacity, which are important reasons underlying radio- and chemoresistance as well as tumor recurrence and metastasis.[100] Cancer stem cells and embryonic stem cells have many similar characteristics, and their stemness can be regulated by the Hippo pathway. In the context of embryogenesis, the developmental process of mouse embryos is stopped when YAP is knocked out.[101] In embryonic stem cells, YAP and TEAD2 can activate OCT4 and Nanog to maintain cell stemness, while inhibition of YAP and TEAD2 can induce differentiation of embryonic stem cells.[102] Besides, in embryonic stem cells that gradually lose their stemness and begin to differentiate, the expression of YAP also decreases.[103] More direct evidence suggests that YAP induces dedifferentiation of differentiated liver cells into pluripotent progenitor cells.[104] These findings suggest that activation of YAP confers the ability of cells to self-renew, indicating that inactivation of the Hippo pathway may promote stem-like properties in cells.
In the context of neoplasia, poorly differentiated tumors have stem-like characteristics and a more aggressive behavior, while benign tumors are overall well-differentiated. Inactivation of the Hippo pathway is closely related to the dedifferentiation and stem-like characteristics of tumors.[23,105,106] Breast cancer cells with low TAZ expression tend to form tumors with a low degree of malignancy (that is, well-differentiated) in mice, while breast cancer cells with high TAZ expression are prone to form poorly differentiated cancers, indicating that high TAZ expression promotes breast cancer stemness.[107] In addition, copy number amplification and high protein expression of YAP were observed in medulloblastoma stem cells.[108] Similarly, in osteosarcoma and glioma, the stemness marker SOX2 can induce inactivation of the Hippo pathway and the activation of YAP by inhibiting NF2 and WWC1, thereby maintaining the stemness of tumor stem cells.[109] These findings suggest that inactivation of the Hippo pathway may promote the self-renewal of cancer stem cells, leading to the formation of poorly differentiated cancers with a more progressive phenotype.
Tumor metastasis
Tumor metastasis refers to the process of tumor cells shedding from the primary tumor, invading blood vessels and surviving under anoikis conditions, and then colonizing to distant tissues forming metastases. Tumor metastasis means that the cancer has reached an advanced stage, with only little hope of cure and limited treatment options, and it is the ultimate cause of death for most cancer patients.[110] The mechanisms underlying tumor metastasis are very complex, involving the regulation of multiple signaling pathways, especially Notch, Wnt, Hedgehog, TGF-β, and other key developmental signaling pathways.[111–114] The Hippo signaling pathway is also closely related to tumor metastasis.[22,115] Clinical data show that low expression of MST1/2 or LATS1/2 is associated with the metastasis of gastric, breast, lung, and other tumors.[116,117] In addition, high expression of YAP/TAZ is also associated with the metastasis of many tumors including colon cancer, gastric cancer, and liver cancer.[118,119] Animal experiments have shown that mutation of a key phosphorylation site (Ser127) of YAP keeps YAP in a continuous activation state, which can induce the metastasis of breast cancer and melanoma in mice.[120] In contrast, knockdown of YAP can inhibit the metastasis of gastric cancer.[121] This suggests that inactivation of the Hippo pathway or activation of YAP largely promotes the metastasis of various tumors.
Tumor metastasis is a multi-step process, and a large number of studies have shown that the Hippo pathway is involved in almost all steps. Firstly, inactivation of the Hippo pathway promotes epithelial–mesenchymal transition (EMT) in tumor cells. Overexpression of YAP/TAZ has been found to induce EMT in various tumor cells,[122,123] while knockdown of YAP/TAZ can inhibit EMT.[124,125] Secondly, YAP promotes cell migration and invasion. For example, multiple studies have shown that knockdown or overexpression of LATS1/2 can promote or inhibit the migration and invasion of tumor cells, respectively.[126,127] Similarly, the effect of YAP/TAZ on the migration and invasion of tumor cells has also been widely reported.[128,129] Thirdly, YAP/TAZ can inhibit anoikis. Circulating tumor cells are in an anoikis state after invading blood vessels, and the ability to acquire anoikis resistance is a key step in tumor metastasis.
The use of chemical drugs to target Hippo signaling for cancer treatment
Most tumors are associated with dysregulated Hippo pathways and altered YAP/TAZ–TEAD activities.[130] Therefore, targeting this pathway using chemical compounds offers an opportunity for cancer treatment (Fig. 4). One potential strategy is to block the YAP/TAZ–TEAD interaction. According to recent in vivo tumor studies with preclinical compounds, inhibiting YAP/TAZ–TEAD interactions may be a feasible strategy. Alternatively, manipulation of upstream stimulators or downstream proteins of YAP/TAZ has also showed significant anticancer effects. The following sections discuss various therapeutic interventions, some of which have shown promise in preliminary studies.
Chemical compounds targeting the Hippo pathway in cancer. Several chemical compounds can target YAP/TAZ, or the upstream regulators of YAP/TAZ, or the downstream effectors of YAP/TAZ, thereby exhibiting antitumor activities. Lat A, Latrunculin A; CytoD, cytochalasin D; VP, verteporfin; PBP, palmitate-binding pocket; VGLL4, Vestigial-like protein 4.
Targeting YAP/TAZ–TEAD activities
A variety of chemicals have been identified to target YAP/TAZ or TEAD. For example, verteporfin (VP) is the first inhibitor found to reduce the growth of tumors in mice by blocking YAP/TAZ–TEAD interactions.[131,132] However, VP has demonstrated proteotoxic properties, suggesting its antitumor effect may not be limited to the inhibition of the YAP–TEAD complex.[133] In addition, considering the short half-life and rapid elimination of VP in the bile, it may not be suitable for clinical use.[134,135] In spite of this, VP has been demonstrated as an effective antitumor agent in advanced pancreatic cancer.[136]
Similar to VP, vinyl sulfonamide derivatives are found to attach to the palmitate-binding pocket (PBP) of TEAD, affecting the interaction between YAP and TEAD. DC-TEADin02, an optimized vinyl sulfonamide derivative, has been shown to be a covalent inhibitor of TEAD auto-palmitoylation with an IC50 value of 197 ± 19 nM. It is noteworthy that DC-TEADin02 inhibits TEAD activity while having a minimal impact on YAP–TEAD interactions.[137] Another TEAD inhibitor, K-975, is capable of disrupting YAP/TAZ–TEAD interactions by covalently binding to a cysteine residue within TEAD’s PBP. Administration of K-975 has been shown to inhibit pleural mesothelioma, which mimics the antitumor effect of YAP deficiency.[138]
Aside from YAP/TAZ, vestigial-like protein 4 (VGLL4) binds to TEADs through their Tondu domains (TDU).[139] VGLL4 is inactivated in gastric cancer and has been recognized as a tumor suppressor.[140] Colorectal cancer (CRC) cells are more likely to proliferate when VGLL4 is inhibited.[141] Mechanistically, VGLL4 acts as an antagonist to YAP by competing with YAP for binding to TEADs through a TUD domain. In animal models, VGLL4 displays an impressive capability to penetrate cells and inhibit YAP-mediated tumorigenesis.[142]
Targeting the upstream stimulators of YAP/TAZ
Besides directly targeting YAP/TAZ, it is also tenable to inhibit YAP/TAZ indirectly by targeting their upstream stimulators. A variety of compounds have the capacity to block the upstream regulators of YAP/TAZ and suppress transcriptional activities of YAP/TAZ by promoting LATS-dependent inhibitory phosphorylation.[143,144] In addition, YAP/TAZ can activate EGFR to induce tumor formation.[145,146] In turn, persistent EGFR signaling leads to the disassembly of core complexes in the Hippo pathway, forming a signaling circuit.[147] Under such circumstances, erlotinib, which acts as an EGFR inhibitor, can disrupt YAP/TAZ activities and may therefore be useful in treating cancers driven by the EGFR-YAP/TAZ axis.[148] In addition, G-protein coupled receptor signaling also influences YAP/TAZ. Blocking Gαq/11 using losartan,[149] or activating Gαs with dihydrexidine,[17] appears to enhance the phosphorylation and consequent degradation of YAP.
Furthermore, actin polymerization facilitates the localization of YAP/TAZ to the nucleus.[66] Accordingly, polymerization modulators including latrunculin A (Lat A) and cytochalasin D (CytoD) can prevent the nuclear translocation of YAP/TAZ.[66,68] Lat A is a toxin derived from Latrunculia magnifica and is an important reagent inducing the depolymerization of actin filaments within living cells.[150] Mechanistically, Lat A attaches to actin monomers and prevents them from polymerization.[150] In gastric cancer, prostate cancer, and breast cancer, Lat A has demonstrated powerful antitumor properties.[151,152] Another actin polymerization inhibitor, CytoD, can diminish the interaction between actin monomers and cofilin.[153] Also, CytoD inhibits cofilin adhering to F-actin and slows down both actin polymerization and depolymerization in cancer cells. However, as discussed previously, YAP/TAZ can be regulated by multiple upstream mechanisms. Thus, targeting one upstream factor may not fully inhibit YAP/TAZ due to the activation of another upstream regulator.
Targeting the downstream proteins transcribed by YAP/TAZ
YAP/TAZ-driven cancer cell proliferation is largely attributed to several oncogenes transcribed by YAP/TAZ. Targeting these downstream proteins has been shown as a promising therapeutic approach. For instance, TAZ can activate the transcription of aldehyde dehydrogenase (ALDH1A1), which facilitates tumor growth and confers stemness in lung carcinoma. Using A37 as an ALDH1A1 inhibitor can reduce the stemness phenotype of lung cells in vitro and tumor formation in vivo.[154] In addition, Axl kinase is transcribed by YAP thus mediating the growth, metastasis, and drug resistance of hepatocellular carcinoma and lung cancer, which can be alleviated by the Axl inhibitor TP0903.[155,156] Of note, TP0903 exhibits significant therapeutic effects not only when used alone but also when combined with other chemotherapeutic agents, such as cisplatin and ATRA.[157]
The YAP–TEAD complex can also induce the transcription of chemokine ligand CXCL5, which contributes to the infiltration of myeloid-derived suppressor cell (MDSC) and the formation of prostate adenocarcinoma.[158] The use of CXCL5 neutralizing antibodies or the CXCL5 receptor antagonist SB255002 blocks MDSC intravasation and tumor growth. This evidence indicates that chemicals targeting Hippo-YAP signaling can be promising anticancer therapeutics.
Conclusion
This article summarizes current knowledge understanding the link between the Hippo pathway and tumor development, which may provide novel insights for the treatment of cancer. However, although significant progress has been made in this area, many questions remain to be further elucidated. For example, YAP may also function as a tumor suppressor gene by inducing cell apoptosis in response to tumor radio- or chemotherapy.[159] This finding implies a possibility that YAP inhibitor may accelerate tumor progression in some cases. In addition, the high toxicity of YAP inhibitor verteporfin limits its application for tumor therapy.[160,161] Although verteporfin theoretically functions by inhibiting the binding of YAP to TEAD, our results suggest that verteporfin also inhibits YAP expression, which is consistent with the reports of other groups.[63,132] These findings suggest that the role of verteporfin is not fully understood and there are potential off-target effects. Furthermore, as a key regulator of development, YAP is required for a variety of physiological processes in normal cells, such as the renewal of the intestinal epithelium.[162] Therefore, cancer therapeutic strategies that directly target the Hippo pathway inevitably affect normal tissues and organs, unless a specific drug delivery approach is available. Another potential strategy is to manipulate YAP target genes (such as ARHGAP29 and BMP4, etc.).[163,164] This method has higher specificity and safety, so it is more likely to become a future direction of cancer drug discovery based on the modulation of Hippo signaling.
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