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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 115-120

Hippo pathway in cancer: Examining its potential


1 Xcode Life Sciences, Chennai, India
2 Department of Biosciences, Jamia Millia Islamia, New Delhi, India
3 School of Biological Science, Apeejay Stya University, Gurugram, Haryana, India
4 Department of Medical Biotechnology, Qassim University, Saudi Arabia
5 Department of Obstetrics and Gynaecology, Maulana Azad Medical College, New Delhi, India

Date of Submission10-May-2021
Date of Acceptance12-Jun-2021
Date of Web Publication23-Feb-2022

Correspondence Address:
Dr. Farah Parveen
Department of Biosciences, Jamia Millia Islamia, New Delhi 110025
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_9_21

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  Abstract 

The Hippo pathway was first discovered and linked to human cancers in the year 2002. It plays a crucial role in the majority of cancers, making it a censorious field for future investigation. Cancer is one of the major health issues, and there is no current cure accessible to efficiently medicate or treat the disease. The disease follows a process of oncogenesis, leading to the transformation of healthy cells (controlled and regulated growth) into cancer cells (uncontrolled and dysregulated growth). Previous studies reveal that the role of the Hippo pathway remains the center in the modulation of developmental biology. The mutated and altered gene expression of LATS1/2 (Large Tumor Suppressor kinase), MST1/2 (Member of Sterile-20 proteins kinase), and YAPs (Yes Associated Proteins), which are the chief factors of the Hippo pathway, basically promotes the invasion and migration of cancer cells. Therefore, targeting the hippo pathway genes is of utmost importance when considering new treatment strategies such as precision or personalized medicine. In this review, we aim at describing how microRNAs, hippo-signaling pathways regulate and maintain the whole hippo signaling.

Keywords: Cancer, Hippo-signaling pathway, LATS1/2, microRNAs, MST1/2, YAPs proteins


How to cite this article:
Najm MZ, Sadaf, Shingatgeri VM, Saha H, Bhattacharya H, Rath A, Verma V, Gupta A, Aloliqi AA, Kashyap P, Parveen F. Hippo pathway in cancer: Examining its potential. J Curr Oncol 2021;4:115-20

How to cite this URL:
Najm MZ, Sadaf, Shingatgeri VM, Saha H, Bhattacharya H, Rath A, Verma V, Gupta A, Aloliqi AA, Kashyap P, Parveen F. Hippo pathway in cancer: Examining its potential. J Curr Oncol [serial online] 2021 [cited 2022 Nov 30];4:115-20. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2021/4/2/115/338063




  Introduction Top


The hippo pathway is one of the major processes, as it controls the organ size in animals by regulating cell proliferation and apoptosis.[1],[2],[3] The pathway is also referred to as the Salvador-Warts-Hippo (SWH) pathway, because all these are the protein kinases that are involved in the signaling. It is a cascade of protein kinases where one protein kinase is phosphorylated by another protein kinase, resulting in the final action. The hippo pathway is extensively studied in drosophila, and its orthologs have been found in mammals too. The pathway achieved its name because of Hippo protein kinase (HPO PK), which mediated the Hippo Signaling. Importantly, mutations in the HPO gene cause inhibitory effects on mitosis, resulting in uncontrolled growth of tissues and leading to cancer.[1],[2],[3]

The orthologs performing the same function in both the species (Drosophila and Mammals) in the Hippo pathway are mentioned in [Table 1]. YORKIE and YAP are nuclear protein kinases, and the Hippo signaling pathway can be initiated by contact inhibition as well as by ligand binding of these cascade proteins.[4],[5]
Table 1: PK in drosophila and mammals performing same activities in hippo pathway[4],[5]

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  Ligand Binding Top


The LPA molecule acts as a ligand and initiates the process of signaling, which enables the activation of G protein that further activates Rho, associated with GTPs, and then the Rho protein via actin modulation finally activates the HPO protein kinase. Further, HPO/MST protein kinase binds and phosphorylates the next protein kinase, that is, SAV/WW45 protein kinase; similarly, these protein kinases bind and phosphorylate WTS/LATS1/2 protein kinases present in line to be phosphorylated. Later, these protein kinases enter the nucleus and deactivate some transcriptional units, that is, YORKIE/YAP protein kinase by phosphorylating them and turning them into their inactive forms.[6] The YORKIE/YAP protein kinases are the transcriptional coactivators, which means that these activate the transcription of certain groups of genes by regulating the transcription of CYCLIN E, DIAP 1 genes. These genes are commonly known as death-associated inhibitors of apoptosis. The CYCLIN E components enable the cell movement from the G1 phase to the S phase of the cell cycle. Therefore, when YORKIE/YAP protein kinase becomes inactive, there is no transcription of cyclin E protein, which, in turn, results in inhibition in mitosis, providing a Halt/Stop signal and leading to the repression of further growth in tissues and this whole process controls the organ size in humans. According to recent studies, any mutation in the genes involved in the Hippo pathway may give rise to uncontrolled tissue growth, resulting in cancer conditions.[7]


  YAP Proteins Top


YAP is known as a yes-associated protein, mapped at chromosome 11q22, and it is an oncoprotein found in the cytoplasm in an inactive form. Once activated, it then translocates to the nucleus, activating the gene transcription required for apoptosis and cell division. YAP and TAZ are mainly accountable for cell growth control and have important regulatory activities in regeneration, stem cell self-renewal, and organ maturity. Both the proteins are regulated by different mechanisms such as extracellular signals and the microenvironment. YAP consists of 488 amino acids and important domains, namely WW and TEA DNA-binding domain, and the regulation of YAP occurs through the Hippo signaling pathway. YAP/TAZ complex is repressed by LATS1 and LATS2, which is an important tumor suppressor in the Hippo pathway. Also, G-protein coupled receptor (GPCR) is the major regulator of YAP and comprises three subunits, α, β, and γ. The Gα11, Gα12, Gα13, Gαi, Gαo, and Gαq trigger YAP and TAZ whereas Gαs suppresses their activity. Numerous pieces of evidence indicate the regulation of the miRNA of YAP, which includes miRNA 31. miRNA 31 is a cancer-causing gene acting through YAP during cancer progression. According to a report, miRNA 31 hampers the luciferase activity of m-RNA linked with LATS2 3′ untranslated region (UTR), a known tumor suppressor. YAP, a cancer-causing protein, regulates transcription factors that control cell cycle and cell division, such as TEAD. Transcriptional enhanced associated domain (TEAD) proteins are linked with the transcription cofactor vestigial-like protein 4 (VGLL4) in a stationary state, which represses target gene expression.[8] Therefore, during activation of the Hippo signaling pathway, the YAP proteins are phosphorylated, which prevents them from moving through the nuclear pores and binding to the TEAD proteins. The YAP was observed at the nuclear level in various cancer cases, such as hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), and ovarian cancer.[8] This further suggests a link between uncontrolled cell division and YAP activity. Nowadays, single treatments via anticancer drugs have a minute effect on the proliferation of cancer cells. The mixture of several drugs is now needed to cease cancer cells by halting the proliferation and inducing apoptosis.[9] The combination of the drugs vemurafenib and trametinib is still not enough for the cancer cells to stop proliferating. They suppress regulatory proteins in the mitogen-activated protein kinase signaling pathway but they are not sufficient enough to cause cancer cell death.[10]

Hence, the YAP protein has a huge function in drug resistance by regulating gene expression, which is responsible for cancer cell survival. These complications have led to the discovery of pharmacogenomics and personalized treatment of cancer by analyzing the whole Hippo pathway and suggesting measures to treat the cancers effectively. YAP alteration in human cancer is shown in [Figure 1].
Figure 1: YAP alteration in human cancers

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  The Function of MicroRNAs in Cancer Top


MicroRNAs belong to the collection of regulative RNAs that are characterized in the three-untranslated vicinity, and they lead to the post-transcription repression via binding in a particular sequential way.[11] The biosynthesis of microRNAs is initiated when RNA polymerase II is transcribed and the microRNA gene organizes itself into the shape of a hairpin loop.[12] The periphery of the hairpin is identified and prepped into a 60-nt stem-loop structure known as the precursor-miRNA through the DGCR8 and endonuclease Drosha. The precursor miRNA is at that time shipped outside the nucleus by RAN-GTP and Exportin-5, wherein the pre-miRNA is additionally arranged into a fully grown miRNA.[13] The fully grown miRNA with the help of extra escort proteins forms in a complex known as RNA-induced silencing complex (RISC).[14] The RISC-linked miRNA led to the region of goal mRNA by the seed sequence, that is, nucleotides two to eight. Essentially, any unique miRNA’s seed area is predicted to aim at lots of mRNAs and every individual mRNA can have hundreds of miRNAs attached to its matching site in 3′UTR.[15],[16] Because of their abundant regulatory abilities, miRNAs are regarded as a huge form of gene controller having the ability to fine-tune gene expression and forcing the advancement of the plethora of diseases[17],[18],[19],[20],[21],[22] [Table 2]. As a whole, microRNAs can affect cancers via the Hippo pathway, which has been summarized in [Figure 2].
Table 2: miRNAs and their role in various cancers

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Figure 2: miRNA and their involvement in the hippo pathway

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  Functions of Hippo Pathway in Cancer Top


In NSCLCs D, if the YAP protein is overexpressed it is mostly linked with progression, poor prediction, and development of the disease. A recent study revealed mutated YAP, which leads to hyperactivity of cancer; it is also linked with lung cancer occurrence.[23] When the studies were done in a subtype of NSCLC, that is, lung adenocarcinoma mouse models, in vivo it was found that the genetic loss of YAP decreases the experimentally induced tumor masses in the mice.[23],[24] If we see a rise in the nuclear activity of YAP protein, it can be caused by a rise or suppression of signals or molecules that negatively control the carcinogenic function of YAP.[25] Studies revealed that if LATS1 is overexpressed it represses NSCLC cell growth, tumor formation, and anchorage-independent growth in mice.[26] Another study also revealed that small interference RNA (siRNA) damages LATS in NSCLC cells, increasing cell proliferation and cell migration.[27] In a cell line study, it was observed that LATS overexpression suppresses lung cancer growth and migration.[28] Also, LATS2 was found to be reduced in function in 60% of NSCLC, and its increased level was noted to negatively regulate YAP, an oncoprotein in NSCLC.[29] The effect of alteration of LATS complex in various cancers is shown in [Figure 3].
Figure 3: LATS1/2 alteration in human cancer

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  YAP Behaves Like an Oncoprotein Top


TEAD and YAP can bind with each other, resulting in the formation of a protein complex known as an oncoprotein, which has a role in the transcription of target downstream genes, including Survivin (an inhibitor of apoptosis) and c-Myc (an oncogene).[30] YAP-TEAD complex (oncoprotein) can be degraded by LATS and MST1 (tumor suppressor) activation via Hippo signaling [Figure 3]. Recent studies demonstrated that porphyrin drugs consisting of verteporfin, protoporphyrin IX can delete the interactions between YAP and TEAD and hematoporphyrin.[31] Another study on chronic myeloid leukemia (CML) concluded that the antitumor effect in CML took place due to the suppression of YAP.[32] YAP silencing may also be targeted in the suppression of cancer cells, as one of the pieces of research demonstrated that a potential treatment strategy for acute myeloid leukemia (AML) is the silencing of YAP.[33]

Angiosarcoma

Angiosarcomas, though rare soft tissue sarcomas, develop in the lining of the blood vessels and often affect the skin, neck, and head. Recent research revealed that YAP is translocated and specifically expressed in the nucleus, and the majority of the patients had inactivated Hippo signaling when YAP is overexpressed. Overall, the YAP’s expression may serve as a potential therapeutic target in human angiosarcomas.[34],[35]


  MST/LATS Activation Top


The Hippo pathway has two major events, which are MST and LST activation. LATS and MST have crucial outcomes on the living organism, as they are epistatically linked to YAPs.[36],[37],[38],[39],[40],[41],[42] The activation of MST/LATS can be prohibited by F-actin; therefore, negative regulators of F-actin can be used to encounter the inhibition, and these indirectly help to activate the MST/LATS activity. The MST activation will help in LATS kinase activation in the phosphorylation of YAPs protein, which inhibits the alliance with cancer-causing TEAD growth-promoting transcription factors [Figure 4]. Many studies reported that this association helps to limit the function of the Hippo pathway in Drosophila melanogaster and mice.[43] Leonel et al. also observed that Y27632, an agent targeting the Hippo pathway, can inhibit the epithelial–mesenchymal transition of BRACA cell lines.[44]
Figure 4: Transcription of YAP and phosphorylation of TAZ take place due to activation of MST1/2 and LATS1/2, leading to proteasomal degradation

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  YAP Regulators Top


The YAP or YAP1 is the transcriptional regulator protein that helps in activating the transcription of a gene that is involved in cell proliferation and also acts as an inhibitor in the Hippo signaling pathway.[45] According to the report by a Korean scientist, Li et al. described that the Decursin proclaims anticancer therapy sensitization and allows the suppression of YAP function that is activated by the upregulation of ubiquitin E3 ligase and LATS1 phosphorylation in HepG2 hepatocellular carcinoma cells.[46] Chai et al. found that some plants have natural tetracyclic triterpene compounds such as Cucurbitacin. Cucurbitacin belongs to the family of Cucurbitaceae and Cruciferae and they have a wide array of use in pharmacological activities such as anticancer, antidiabetic, and antioxidant uses. Cucurbitacin B has an anticancer function in colorectal cancer cells by hindering YAPs.[47] From the earlier cited few examples and experiments, we can conclude that YAP regulators are being targeted in the Hippo-signaling pathway to achieve maximum positive outcomes in cancer therapy.


  Inhibition of YAP-TEAD Interaction Top


Research on the TEAD transcription factor family set about with the recognition of TEAD1, which was the first attempt to recognize nuclear proteins that could switch on transcription and bind to the simian vacuolating virus 40 (SV40) enhancers.[48] TEADs have evolved vastly from the work that focused on TEADs in the background of the Hippo-signaling pathway.[49] TEAD transcriptional function is mainly said to be modulated by the absence or presence of nuclear YAP. YAP has a specific inhibitor named Verteporfin (VP), which can chunk the interlinkage between TEAD and YAP to put a stop to YAP’s function.[50] Some scientists have revealed that Verteporfin can prevent cancer cell proliferation in various types of tumors, including endometrial, ovarian cancers, and retinoblastoma. Apart from Verteporfin, hematoporphyrin and protoporphyrin 9 belong to the family of the porphyrin, and both are presently recognized as a suppressor of YAP-TEAD interlinked in the xenograft mouse model,[51] which can be the succeeding nominee for medicating cancer. To sum up, in terms of cancer treatment, LATS 2, an important suppressor on the YAP-TEAD complex, was immensely downregulated in breast cancer tissues.[52] The downregulation may have resulted in the loss of activity of LATS2 to suppress YAP-TEAD complex and thus targeting YAP-TEAD in patients with breast cancer can be considered a therapy of choice.


  Conclusion Top


The past few years of work done by the science fraternities have become prevalent in understanding the genetic alterations in carcinogenesis and due to this substantial advancement in cancer research, several medications have been developed in recent years. Various types of medications that can inhibit the Hippo pathway and are used in cancer treatment are introduced in the market. These special targeting drugs are designed in such a manner that they can promote the survival rate of patients with cancer and can act as a resistance for the inhibitors. A huge variety of cancers have shown higher expression of TAZ and YAP, and suppressing them may lead to cancer treatment. Nevertheless, based on the scientist’s perception, YAP alone could be a cancer-causing protein in malignant hematologic tumors. Other main elements of the Hippo pathway are controlled by a complicated network of signaling pathways, YAP, and microRNAs. The drugs that targeted the Hippo pathways have been recognized to cure oncogenic diseases. Although monumental research has reported additional knowledge on the Hippo pathway, a lot remains unknown and needs to be discovered.

Financial support and sponsorship

The grant for this project was provided by the Department of Science and Technology (DST) (GRANT NO: SR/WOS-A/LS-525/2016), Government of India, New Delhi, India.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]


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Ligand Binding
YAP Proteins
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Functions of Hip...
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MST/LATS Activation
YAP Regulators
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