Role and mechanism of YAP1 in pan-cancer

Role and mechanism of YAP1 in pan-cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Role and mechanism of YAP1 in pan-cancer Yufan Xu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6883851/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Backgrounds and aims: Cancers threaten health and life of patients with tumors. It is important to diagnose and treat various tumors as early as possible. However, there is limited early biomarkers for cancers. Yes-associated protein 1 (Yap1) is involved in the Hippo signaling pathway, and thus regulating development and cell growth. Yap1’s role in pan-cancer remains to be investigated. The objective of the present investigation was to explore the possible role and mechanism of Yap1 in pan-cancer. Methods Timer2.0 and GEPIA were employed to analyze the expression of YAP1 in cancerous tissues and controls; HPA was used to study the expression of YAP1 in different tissues and subcellular location; for survival analysis, GEPIA, the HPA, and KM plotter were utilized to generate survival curves, evaluating the prognostic significance of YAP1 expression; cBioPortal was used to investigate the mutation frequency and genetic alterations of YAP1 ; AlphaFold was applied to predict the structure of Yap1 and identify potential pathogenic sites, while PhosphoNet helped in predicting and analyzing phosphorylation sites of Yap1; the STRING was employed to explore Yap1's interacting proteins. Results The levels of YAP1 in tumor tissues were mostly lower than controls; Yap1 was ubiquitously expressed and located in cytosol; YAP1 is a significant predictor of survival in PAAD and KIRC; its expression is closely linked to immune infiltration; YAP1 exhibits a high mutation frequency across various cancer types; many phosphorylation sites especially S276 in Yap1 is highly a phosphorylation site; Yap1 interacts with proteins including Last1 and Last2 associated with the hypoxia pathway. Conclusion Yap1 is significantly associated with pan-cancer, which may serve as a potential biomarker of cancers. Health sciences/Oncology/Cancer/Cancer genetics Health sciences/Oncology/Cancer/Cancer genomics Health sciences/Oncology/Cancer/Cancer therapy Health sciences/Oncology/Cancer/Tumour biomarkers Health sciences/Oncology/Cancer/Tumour immunology Health sciences/Oncology/Cancer YAP1 pan-cancer survival time biomarker immune infiltration Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 1 Introduction Cancers threaten health and life of patients with cancers. Recently its new case and deaths persistently increased ( 1 ). 19.3 million new cancer cases and nearly 10 million cancer-related deaths were reported in 2020 and are expected to increase by 47% to 28.4 million cases by 2040 ( 2 , 3 ). Although surgery, immune, and gene combination therapy have had some effect, there is limited early biomarkers for cancers ( 4 ). It is important to diagnose and treat various tumors as early as possible. Early biomarkers should be investigated and put into use ( 5 ). Yes-associated protein 1 (Yap1), is a key effector in the Hippo signaling pathway, and it plays a crucial role in regulating cell growth, apoptosis, and differentiation ( 6 ). The role of YAP1 in the initiation, progression, and metastasis of pan-cancer has received more and more attention ( 7 ). As a transcriptional co-activator, the abnormal activation or dysregulation of YAP1 is tightly related to tumor’s cell proliferation, immune evasion, and resistance ( 8 ). YAP1 ’s mechanism is complex and diverse, including crosstalk with other signaling pathways and transcriptional regulation of downstream target genes ( 9 , 10 ). YAP1 affect tumor cell’s biological behavior by regulating cell’s cyclin, apoptosis-associated speck-like protein and epithelial-mesenchymal transition (EMT)-related genes ( 11 ). Yap1 is also involved in regulating the way of forming the microenvironment of tumor, affecting immune cell infiltration and function ( 12 ). YAP1 has significant prognostic value across various cancers and may serve as a potential biomarker for cancer immunotherapy ( 13 ). YAP1 in pan-cancer remains to be investigated. The objective of the present investigation was to explore the possible role and mechanism of YAP1 in pan-cancer. Mutiple databases including Timer2.0, GEPIA, cBioPortal, PhosphoNet, et al. Were employed to analyze the expression, variations, prognosis, et al. The data demonstrate that Yap1 is involved in cancers, and it may be a potential biomarker. 2 Methods 2.1 Expression difference and survival analysis GEPIA ( http://gepia.cancer-pku.cn/index.html ) is an important platform for analyzing expression levels of any interested gene in diverse tumor tissues and their respective controls ( 14 ). To study the possible role of YAP1 in cancers, GEPIA website was opened. The gene analysis module was selected, and “YAP1” was put in the search and it was submitted. TIMER2.0 (timer.cistrome.org) is also an platform specializing in Immune Association, Cancer Exploration and Immune Estimation ( 15 – 17 ). To check the difference between cancer tissues and controls, TIMER2.0 website was opened. Differential gene expression in the “Gene_DE module” between tumor and normal tissue was selected, and “YAP1” was put in the search and it was submitted. HPA ( https://www.proteinatlas.org ) is a public database providing details of expression of YAP1 mRNA and proteins ( 18 ), its distribution and subcellular location in different tissues and cells in this study. First of all, “YAP1” was put in the search and submitted. After choosing “YAP1” on the page, “TISSUE” was selected for checking on RNA and protein expression summary; “SUB CELL” was selected and U 2 OS was chosen to show the distribution of protein expression in cells; and “CANCER” was selected and lung cancer was selected to check on the pathological section of tumor tissues. For survival analysis, first, the GEPIA website was opened, and the module of Gene Expression was selected. Then, “ YAP1 ” was put in the search and submitted, and the survival module was also chosen. Second, the HPA database was used to analyze the survival of the cancer patients with different expression patterns of YAP1. “ YAP1 ” was typed and submitted, and survival plots were obtained. Third, the survival plots of YAP1 were chosen and download from KM plotter ( https://KMplotter.com/analysis/ ) ( 19 , 20 ). “YAP1” was put in the search and it was submitted. 2.2 Correlation analysis of immune infiltration TIMER2.0 was can also used to estimate the connection of YAP1’s immune infiltration, the website was opened and “Immune” was chosen. “YAP1” and “T cell CD4+” was put in the search and it was submitted. 2.3 Gene variation and protein structure prediction cBioPortal ( http://www.cbioportal.org/ ) is an important public platform constructed by Memorial Sloan Kettering Cancer Center (MSK) ( 21 – 23 ). Based on the TCGA database, the cBioPortal integrates data mining, integration, and visualization comprehensively. To show alteration frequency of YAP1 and to show mutations of YAP1 , “YAP1” was put in the search and it was submitted. AlphaFold ( https://alphafold.ebi.ac.uk/ ) can predict the unknown structures of proteins based on known structures (24, 25). AlphaFold’s website was accessed and “YAP1” was put in the search and it was submitted. YAP1 ’s corresponding protein’s structure was shown, also the pathogenicity heatmap can be seen. 2.4 Prediction of phosphorylation sites and protein interactions Phosphonet ( www.phosphonet.ca ) is a website that is adopted to predict and analyze phosphorylation sites of any protein. For further study of YAP1 ’s phosphorylation site, Phosphonet’s website was opened. “YAP1” was put in the search and it was submitted. String ( https://cn.string-db.org ) is a website that analyzes Protein-Protein interaction ( 26 – 38 ). To investigate the interaction between Yap1 and other proteins, String’s website was opened and “YAP1” was put in the search and it was submitted. 3 Results 3.1 YAP1’s expression was reduce in multiple cancers YAP1 is known to play a role in the development and progression of multiple cancers as a transcriptional regulator of this signaling pathway ( 39 – 41 ). First of all, the patterns of YAP1 in cancer tissues were investigated by applying GEPIA. As exhibited, 31 pairs of cancers and their respective controls were studied, and the levels YAP1 in 17 types of cancer tissues were significantly lower than the controls, such as ACC (Adrenocortical carcinoma), BLCA (Bladder Urothelial Carcinoma), and UCEC (Uterine Corpus Endometrial Carcinoma), etc (Fig. 1 A and B). In comparison, the expressions of YAP1 in DLBC (Lymphoid Neoplasm Diffuse Large B-cell Lymphoma), GBM (Glioblastoma multiforme) and PAAD (Pancreatic adenocarcinoma), etc. were significantly higher than the healthy controls. As shown in Timer2.0 results, among the 23 pairs of cancers and their respective controls, the mRNA expression patterns of YAP1 were significantly lower in 14 different types of cancers comparing to the normal controls. Additionally, 4 cancers exhibited significantly higher levels than their respective controls ( P < 0.05), and the remaining 10 tissues showed significantly lower levels than the normal controls ( P < 0.001) among these 23 pairs, such as BLCA, BRCA (Breast invasive carcinoma), CHOL (Cholangiocarcinoma), etc (Fig. 1 C). 3.2 YAP1 was widely expressed and nuclear-localized Next, the expression of YAP1 in normal organs, tissues and cells were also explored in the current investigation by employing HPA. As illustrated in Fig. 2 A, YAP1 mRNA and protein patterns were evident and ubiquitously appeared, although there were variations between distinct tissues and organs. Both the mRNA and protein levels of YAP1 were high in muscle tissues, whereas the patterns were low in the eye. The subcellular location of YAP1 in cultured cells were investigated by using HPA. As displayed in the Fig. 2 B, YAP1 was mainly located in the nuclei in U 2 OS cells. From the pathological section of a 75 male patient who has lung cancer, it was clear that YAP1 was expressed in the cancer tissue (Fig. 2 C). The staining level is medium and staining quantity > 75%. 3.3 YAP1’s survival analysis in PAAD and KIRS As exhibited in the Fig. 3 , PAAD and KIRS (Kidney renal clear cell carcinoma) were both statistically significant in GEPIA, HPA and KM plotter (P PAAD =0.005, 0.002, < 0.001; PKIRS = 0.004, < 0.001, 0.028) (Fig. 3 A-F). Survival plots showed that YAP1 ’s expression was poor prognostic indicator for PAAD, but favorable prognostic indicator for KIRS. 3.4 Expression correlated with immune infiltration As it was shown in heat map, the expression of YAP1 had significant connections with T-cell CD4+’s immune infiltration for most of cancers, and most of connections were positive correlations, such as DLBC, ESCA (Esophageal carcinoma), GBM, etc (Fig. 4 A). Figure 4 B also shows that the expression of YAP1 has changed significant with infiltration level rise. 3.5 YAP1 shows high alteration frequency in most of cancers As it was shown in Fig. 5 A, many cancers showed alteration frequency of YAP1 . It was obvious that the most common alteration was Amplification, and Cervical squamous cell carcinoma had the highest alteration frequency (> 10%). Phosphorylation plays critical roles in regulating gene expression. Therefore, various point mutations especially the variation of S276N may cause cancers (Fig. 5 B). 3.6 Many high-confidence phosphorylation sites were identified As shown in Fig. 6 , YAP1 had 33 phosphorylation sites, such as S21, S31, S61, etc. Compared the result in Fig. 5 B and Fig. 6 , S61, T63, S94, S103, S105, T110, T114, T119, S127, S131, S138, T141, T143, T145, S149, T154, T156, S163, S164, S217, S236, S382 appeared to be phosphorylation site both in cBioportal and Phosphonet, these phosphorylation sites’ chances to be YAP1’s phosphorylation sites were extremely high. 3.7 Structure features and mutation indicated pathogenicity The Yap1’s corresponding protein’s structure was shown (Fig. 7 A ) . Many important part such as α-helix and β-pleated sheet had high confidence. As for the heatmap, it was obvious that many sites were pathogenic (Fig. 7 B). Compared Fig. 5 B and Fig. 7 B, and used high confidence sections in Fig. 7 A, some of mutation sites, such as F95C, R262M and Q322K could be highly connected with cancers. 3.8 Yap1 interacts with Hypoxic pathway-associated proteins As exhibited in Fig. 8 , Yap1 has some interacting protein, such as LATS1, LATS2, etc. LATS1 and LATS2 were both very important parts of Hippo signaling pathway-a hypoxic pathway. Different color lines meant Known Interactions, Predicted Interactions and others. 4 Discussion There are several findings in this study: first, YAP1 is ubiquitously expressed in both normal tissues and disease tissues, and its level is lower in cancerous tissues; second, YAP1 is located in nuclei generally; third, the expression of YAP1 is significant correlated with immune infiltration of the immune cells in most types of tumors; fourth, expression of YAP1 is negatively and significantly associated with the survival of cancer patients largely; fifth, there are different variations of YAP1 in various cancers, and the R331W in YAP1 is observed in patients with cancer; furthermore, YAP1 structure is predicted and some pathogenetic points are revealed, which is associated with phosphorylation modification. In addition, the interacting proteins of LAST1/2 are the partners of YAP1. These data indicate that YAP1 is associated with cancers. The biggest novelty of this study is that YAP1 was correlated with various cancers, and some hotspots of YAP1 in cancers are predicted as pathogenetic points in tumors, indicating that it may serve as a possible biomarker in clinics. YAP1 levels in cancerous tissues of colorectal cancers were higher than the controls( 42 ), which is consistent with the findings of this study that YAP1 was higher than the respective controls in READ ( 42 ). The data in Fig. 2 B in the current investigation exhibit that Yap1 is expressed in the nuclei, which is further supported by previous studies that Yap1 is located in nuclei ( 42 , 43 ). The YAP1 ’s expression level was negatively correlated with the immune infiltration of the CD 8 + T cells of the prostate cancer ( 44 ). In comparison, the pattern of YAP1 was significantly associated with the immune infiltration of the CD 4 + T cells in BRCA in the current investigation, suggesting these data were consistent with each other. The high levels of YAP1 were significant correlated with unfavorable overall survival in glioma patients ( 45 ), supporting the data in this study. R331W variation in YAP1 was discovered and confirmed in the patients with lung cancer ( 46 ) (R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability), which was also validated in our study in Fig. 5 . There are various limitations in this analysis of bioinformatics. First, there is only bioinformatic analysis, and there is little experimental data. Second, there is limited case numbers. Third, there are some conflicting data regarding the present investigation and previous investigations. In future, cell and animal studies should be done to validate the findings in this study. Furthermore, more cases should be recruited to further confirm the conclusion. Additionally, it should be made clear the conflicting conclusions. 5 Conclusion In summary, YAP1 expressed differently across various cancers, with significantly reduced expression in multiple tissues compared to controls. It expressed widely among organs and primarily localized in the nucleus. In some specific cancers such as PAAD and KIRC, YAP1 ’s expression level was associated with prognosis. Furthermore, YAP1 showed connections with immune cell infiltration. And genomic analysis indicated frequent alternations in YAP1 , and many mutation sites were located in high-confidence structural regions. Multiple phosphorylation sites were identified with high predictive confidence as well. Lastly, Yap1 was shown to interact with some key proteins involved in cancer signaling pathway. These findings provide a comprehensive overview of YAP1 ’s expression, prognostic relevance, molecular characteristics, and interaction profile. Yap1 is significantly associated with pan-cancer, which may serve as a potential biomarker of cancers. Declarations Ethics Approval and Informed Consent The data used in this study were obtained from publicly available databases, which contain anonymized human data with no personally identifiable information. Therefore, no additional ethical approval or informed consent was required. Author Contributions Yufan Xu: Conceptualization, Investigation, Methodology, Software, Data curation, Formal analysis, Visualization, Writing - original draft, Writing - review & editing, Validation, Funding acquisition, Project administration, Supervision. Competing Interests The author declares no competing interests. Funding No specific funding was received for this research. Consent for Publication Not applicable. Acknowledgements The author sincerely thanks the developers and curators of GEPIA, TIMER2.0, HPA, KM Plotter, cBioPortal, AlphaFold, PhosphoNet, and STRING databases for providing open access to their valuable data and analysis platforms. Data Availability All data analyzed in this study were obtained from publicly available databases, including TIMER2.0 (http://timer.cistrome.org/), GEPIA (http://gepia.cancer-pku.cn/), KM plotter (https://kmplot.com), cBioPortal (https://www.cbioportal.org/), the Human Protein Atlas (https://www.proteinatlas.org/), AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/), PhosphoNet (https://www.phosphonet.ca/), and STRING (https://string-db.org/). The processed data and results that support the findings of this study are available within the manuscript. No new datasets were generated during the current study. References Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6883851","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":485125357,"identity":"4349ad6b-fe4d-42fc-ae1d-07022e2dacd4","order_by":0,"name":"Yufan Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYFACxgdA4gADA3tj44MPxGlhNoBo4TncbDiDNC0S6W3SHMRoMLiRzPzh54478uaSDxukGRjs5HQbCGiRnJHMJtl75pnhztmJDcYFDMnGZgcIaOGXyD/GwNt2mHHD7cSG5BkMBxK3EdLCJpHM/PFv22H7DTcPNhzmIUYLv0QygzTQlsQNNxgbm4nSItnzmE1atu1Z8oYzic2MMwyI8IvBcaDD3rbdsd1w/PjzHx8q7OQIamEQSEAxgZByEOAnaOgoGAWjYBSMeAAAZFRJW2LRBGoAAAAASUVORK5CYII=","orcid":"","institution":"Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yufan","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2025-06-13 02:08:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6883851/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6883851/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87033550,"identity":"4c236d71-b529-469f-876c-7874185f6b0a","added_by":"auto","created_at":"2025-07-18 13:07:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":278119,"visible":true,"origin":"","legend":"\u003cp\u003eThe levels of \u003cem\u003eYAP1\u003c/em\u003e were lower in cancer tissues generally.\u003c/p\u003e\n\u003cp\u003e(A) The expressions of \u003cem\u003eYAP1\u003c/em\u003e in cancer tissues and healthy control tissues were analyzed by employing GEPIA (Dot plot).\u003c/p\u003e\n\u003cp\u003e(B) The levels of \u003cem\u003eYAP1\u003c/em\u003e in tumors and controls were investigated by GEPIA (Bar plot).\u003c/p\u003e\n\u003cp\u003e(C) \u003cem\u003eYAP1 \u003c/em\u003ebetween cancer and control samples was studied by using Timer2.0. * \u003cem\u003eP\u003c/em\u003e ＜ 0.05. ** \u003cem\u003eP\u003c/em\u003e ＜0.01.\u003c/p\u003e\n\u003cp\u003e***\u003cem\u003eP\u003c/em\u003e ＜ 0.001.\u003c/p\u003e\n\u003cp\u003eACC (Adrenocortical carcinoma), BLCA (Bladder Urothelial Carcinoma), BRCA (Breast invasive carcinoma), CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (Cholangiocarcinoma), COAD (Colon adenocarcinoma), DLBC (Lymphoid Neoplasm Diffuse Large B-cell Lymphoma), ESCA (Esophageal carcinoma), GBM (Glioblastoma multiforme), HNSC (Head and Neck squamous cell carcinoma), KICH (Kidney Chromophobe), KIRC (Kidney renal clear cell carcinoma), KIRP (Kidney renal papillary cell carcinoma), LAML (Acute Myeloid Leukemia), LGG (Brain Lower Grade Glioma), LIHC (Liver hepatocellular carcinoma), LUAD (Lung adenocarcinoma), LUSC (Lung squamous cell carcinoma), MESO (Mesothelioma), OV (Ovarian serous cystadenocarcinoma), PAAD (Pancreatic adenocarcinoma), PCPG (Pheochromocytoma and Paraganglioma), PRAD (Prostate adenocarcinoma), READ (Rectum adenocarcinoma), SARC (Sarcoma), SKCM (Skin Cutaneous Melanoma), STAD (Stomach adenocarcinoma), TGCT (Testicular Germ Cell Tumors), THCA (Thyroid carcinoma), THYM (Thymoma), UCEC (Uterine Corpus Endometrial Carcinoma), UCS (Uterine Carcinosarcoma), UVM (Uveal Melanoma).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/42b74af96fd91382907f446a.png"},{"id":87033552,"identity":"50cebb3e-94a5-446d-a4d6-c77bb1ba41ee","added_by":"auto","created_at":"2025-07-18 13:07:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":258998,"visible":true,"origin":"","legend":"\u003cp\u003eExpression of \u003cem\u003eYAP1 \u003c/em\u003ein tissues and cells.\u003c/p\u003e\n\u003cp\u003e(A) RNA and protein are appeared in almost all tissues.\u003c/p\u003e\n\u003cp\u003e(B) \u003cem\u003eYAP1\u003c/em\u003e is primarily expressed in the cell nucleus.\u003c/p\u003e\n\u003cp\u003e(C) \u003cem\u003eYAP1\u003c/em\u003e was widely infiltrated in the cancer tissue.\u003c/p\u003e\n\u003cp\u003eTPM (Transcripts per million readings).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/b1d0ed38b071ea65f4c09467.png"},{"id":87033553,"identity":"4d74ef38-87dd-4345-8972-62f61d5eb8aa","added_by":"auto","created_at":"2025-07-18 13:07:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":161573,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival plots of PAAD and KIRS from GEPIA, Human Protein Atlas and KM plotter.\u003c/p\u003e\n\u003cp\u003e(A) The survival analysis of PAAD by employing GEPIA..\u003c/p\u003e\n\u003cp\u003e(B) \u003cem\u003eYAP1\u003c/em\u003e expression is significantly correlated with survival of the cancer patients with KIRS.\u003c/p\u003e\n\u003cp\u003e(C) YAP1 serves as a negative prognostic factor for PAAD in HPA analysis.\u003c/p\u003e\n\u003cp\u003e(D) PAAD is a poor, while YAP1 expression correlates with a favorable prognostic factor in KIRS.\u003c/p\u003e\n\u003cp\u003e(E) KM plotter confirm YAP1 level is associated with poor patient outcomes in PAAD.\u003c/p\u003e\n\u003cp\u003e(F) YAP1 expression serving as a positive prognostic indicator for KIRS by KM plotter analysis.\u003c/p\u003e\n\u003cp\u003eTPM (Transcripts per million readings), HR (hazard ratio), PAAD (Pancreatic adenocarcinoma), KIRC (Kidney renal clear cell carcinoma).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/f91740215a0d0608ec3f3483.png"},{"id":87033554,"identity":"b09de70b-5861-491a-baad-60acdf8f6a5f","added_by":"auto","created_at":"2025-07-18 13:07:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":277049,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eYAP1\u003c/em\u003e’s connections with immune infiltration.\u003c/p\u003e\n\u003cp\u003e(A) \u003cem\u003eYAP1\u003c/em\u003e has significant connections with T-cell CD4+’s immune infiltration.\u003c/p\u003e\n\u003cp\u003e(B) The expression of \u003cem\u003eYAP1\u003c/em\u003e has changed significant with infiltration level rise\u003cem\u003eYAP1\u003c/em\u003e shows high alteration frequency in BRCA.\u003c/p\u003e\n\u003cp\u003e(C) ACC (Adrenocortical carcinoma), BLCA (Bladder Urothelial Carcinoma), BRCA (Breast invasive carcinoma), CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (Cholangiocarcinoma), COAD (Colon adenocarcinoma), DLBC (Lymphoid Neoplasm Diffuse Large B-cell Lymphoma), ESCA (Esophageal carcinoma), GBM (Glioblastoma multiforme), HNSC (Head and Neck squamous cell carcinoma), KICH (Kidney Chromophobe), KIRC (Kidney renal clear cell carcinoma), KIRP (Kidney renal papillary cell carcinoma), LAML (Acute Myeloid Leukemia), LGG (Brain Lower Grade Glioma), LIHC (Liver hepatocellular carcinoma), LUAD (Lung adenocarcinoma), LUSC (Lung squamous cell carcinoma), MESO (Mesothelioma), OV (Ovarian serous cystadenocarcinoma), PAAD (Pancreatic adenocarcinoma), PCPG (Pheochromocytoma and Paraganglioma), PRAD (Prostate adenocarcinoma), READ (Rectum adenocarcinoma), SARC (Sarcoma), SKCM (Skin Cutaneous Melanoma), STAD (Stomach adenocarcinoma), TGCT (Testicular Germ Cell Tumors), THCA (Thyroid carcinoma), THYM (Thymoma), UCEC (Uterine Corpus Endometrial Carcinoma), UCS (Uterine Carcinosarcoma), UVM (Uveal Melanoma).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/1448ad98be36ee09363b40de.png"},{"id":87033559,"identity":"7345f9e0-a5d5-4f2e-8974-8adf17b2828d","added_by":"auto","created_at":"2025-07-18 13:07:00","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":183961,"visible":true,"origin":"","legend":"\u003cp\u003eMutations of \u003cem\u003eYAP1 \u003c/em\u003eare common in cancers and it is multisided.\u003c/p\u003e\n\u003cp\u003e(A) \u003cem\u003eYAP1\u003c/em\u003eshows high alteration frequency in most of cancers.\u003c/p\u003e\n\u003cp\u003e(B) Point Mutations appeared in Yap1 Point Mutations contribute to cancer development.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/e11838a0b142c223d3c86561.png"},{"id":87035582,"identity":"3516911e-848f-497e-8e21-f97e6f72d0f9","added_by":"auto","created_at":"2025-07-18 13:15:00","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":227785,"visible":true,"origin":"","legend":"\u003cp\u003ephosphorylation sites’ result by Phosphonet.\u003c/p\u003e\n\u003cp\u003eExpt. conf. (Experimental Confidence), Effect (Effect of Phosphorylation), Kinase (Kinase), PPase (Phosphatase), Kinexus Products (Kinexus Antibodies or Arrays), Ref. (References), Evol. (Evolutionary Conservation), Kinase Pred. (Kinase Prediction), P-site Match (Phosphorylation Site Match).\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/0581729e6355b08149a5cf0e.png"},{"id":87033571,"identity":"281a13ed-659f-4c39-b7f7-295e67894a54","added_by":"auto","created_at":"2025-07-18 13:07:00","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":166358,"visible":true,"origin":"","legend":"\u003cp\u003eStructure and pathogenic performance.\u003c/p\u003e\n\u003cp\u003e(A) Structure of Yap1’s corresponding protein.\u003c/p\u003e\n\u003cp\u003e(B) Many sites of Yap1 are pathogenic.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/ea2ce0ef6a68fd989783581b.png"},{"id":87036808,"identity":"643d87bc-ead2-4c2a-a21f-bb5d8ccf8a11","added_by":"auto","created_at":"2025-07-18 13:23:00","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":195317,"visible":true,"origin":"","legend":"\u003cp\u003eYAP1’s Protein-Protein interaction.\u003c/p\u003e\n\u003cp\u003eNode Color\u003c/p\u003e\n\u003cp\u003eRed nodes: Query proteins and first shell of interactors\u003c/p\u003e\n\u003cp\u003eWhite nodes: Second shell of interactors\u003c/p\u003e\n\u003cp\u003eNode Content\u003c/p\u003e\n\u003cp\u003eEmpty nodes: Proteins of unknown 3D structure\u003c/p\u003e\n\u003cp\u003eFilled nodes: Proteins with known or predicted 3D structure\u003c/p\u003e\n\u003cp\u003eKnown Interactions\u003c/p\u003e\n\u003cp\u003ePink edges: From curated databases\u003c/p\u003e\n\u003cp\u003eBlue edges: Experimentally determined\u003c/p\u003e\n\u003cp\u003ePredicted Interactions\u003c/p\u003e\n\u003cp\u003eGreen edges: Gene neighborhood\u003c/p\u003e\n\u003cp\u003eRed edges: Gene fusions\u003c/p\u003e\n\u003cp\u003eDark blue edges: Gene co-occurrence\u003c/p\u003e\n\u003cp\u003eOther Interactions\u003c/p\u003e\n\u003cp\u003eLight green edges: Textmining\u003c/p\u003e\n\u003cp\u003eBlack edges: Co-expression\u003c/p\u003e\n\u003cp\u003eLight purple edges: Protein homology\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/c8cbb514603a56c9875dac4f.png"},{"id":98339253,"identity":"73350471-447d-46a7-acc0-e6465df24fa4","added_by":"auto","created_at":"2025-12-16 16:54:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2272423,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6883851/v1/79fedaf6-5ea9-45d5-826e-341872325746.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Role and mechanism of YAP1 in pan-cancer","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eCancers threaten health and life of patients with cancers. Recently its new case and deaths persistently increased (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). 19.3\u0026nbsp;million new cancer cases and nearly 10\u0026nbsp;million cancer-related deaths were reported in 2020 and are expected to increase by 47% to 28.4\u0026nbsp;million cases by 2040 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Although surgery, immune, and gene combination therapy have had some effect, there is limited early biomarkers for cancers (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). It is important to diagnose and treat various tumors as early as possible. Early biomarkers should be investigated and put into use (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eYes-associated protein 1 (Yap1), is a key effector in the Hippo signaling pathway, and it plays a crucial role in regulating cell growth, apoptosis, and differentiation (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The role of YAP1 in the initiation, progression, and metastasis of pan-cancer has received more and more attention (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). As a transcriptional co-activator, the abnormal activation or dysregulation of \u003cem\u003eYAP1\u003c/em\u003e is tightly related to tumor\u0026rsquo;s cell proliferation, immune evasion, and resistance (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). \u003cem\u003eYAP1\u003c/em\u003e\u0026rsquo;s mechanism is complex and diverse, including crosstalk with other signaling pathways and transcriptional regulation of downstream target genes (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). YAP1 affect tumor cell\u0026rsquo;s biological behavior by regulating cell\u0026rsquo;s cyclin, apoptosis-associated speck-like protein and epithelial-mesenchymal transition (EMT)-related genes (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Yap1 is also involved in regulating the way of forming the microenvironment of tumor, affecting immune cell infiltration and function (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). YAP1 has significant prognostic value across various cancers and may serve as a potential biomarker for cancer immunotherapy (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eYAP1 in pan-cancer remains to be investigated. The objective of the present investigation was to explore the possible role and mechanism of YAP1 in pan-cancer. Mutiple databases including Timer2.0, GEPIA, cBioPortal, PhosphoNet, et al. Were employed to analyze the expression, variations, prognosis, et al. The data demonstrate that Yap1 is involved in cancers, and it may be a potential biomarker.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1 Expression difference and survival analysis\u003c/h2\u003e\n \u003cp\u003eGEPIA (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://gepia.cancer-pku.cn/index.html\u003c/span\u003e\u003c/span\u003e) is an important platform for analyzing expression levels of any interested gene in diverse tumor tissues and their respective controls (\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e). To study the possible role of \u003cem\u003eYAP1\u003c/em\u003e in cancers, GEPIA website was opened. The gene analysis module was selected, and \u0026ldquo;YAP1\u0026rdquo; was put in the search and it was submitted.\u003c/p\u003e\n \u003cp\u003eTIMER2.0 (timer.cistrome.org) is also an platform specializing in Immune Association, Cancer Exploration and Immune Estimation (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e). To check the difference between cancer tissues and controls, TIMER2.0 website was opened. Differential gene expression in the \u0026ldquo;Gene_DE module\u0026rdquo; between tumor and normal tissue was selected, and \u0026ldquo;YAP1\u0026rdquo; was put in the search and it was submitted.\u003c/p\u003e\n \u003cp\u003eHPA (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.proteinatlas.org\u003c/span\u003e\u003c/span\u003e) is a public database providing details of expression of YAP1 mRNA and proteins (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e), its distribution and subcellular location in different tissues and cells in this study. First of all, \u0026ldquo;YAP1\u0026rdquo; was put in the search and submitted. After choosing \u0026ldquo;YAP1\u0026rdquo; on the page, \u0026ldquo;TISSUE\u0026rdquo; was selected for checking on RNA and protein expression summary; \u0026ldquo;SUB CELL\u0026rdquo; was selected and U\u003csub\u003e2\u003c/sub\u003eOS was chosen to show the distribution of protein expression in cells; and \u0026ldquo;CANCER\u0026rdquo; was selected and lung cancer was selected to check on the pathological section of tumor tissues.\u003c/p\u003e\n \u003cp\u003eFor survival analysis, first, the GEPIA website was opened, and the module of Gene Expression was selected. Then, \u0026ldquo;\u003cem\u003eYAP1\u003c/em\u003e\u0026rdquo; was put in the search and submitted, and the survival module was also chosen. Second, the HPA database was used to analyze the survival of the cancer patients with different expression patterns of YAP1. \u0026ldquo;\u003cem\u003eYAP1\u003c/em\u003e\u0026rdquo; was typed and submitted, and survival plots were obtained. Third, the survival plots of \u003cem\u003eYAP1\u003c/em\u003e were chosen and download from KM plotter (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://KMplotter.com/analysis/\u003c/span\u003e\u003c/span\u003e) (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e). \u0026ldquo;YAP1\u0026rdquo; was put in the search and it was submitted.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Correlation analysis of immune infiltration\u003c/h2\u003e\n \u003cp\u003eTIMER2.0 was can also used to estimate the connection of YAP1\u0026rsquo;s immune infiltration, the website was opened and \u0026ldquo;Immune\u0026rdquo; was chosen. \u0026ldquo;YAP1\u0026rdquo; and \u0026ldquo;T cell CD4+\u0026rdquo; was put in the search and it was submitted.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 Gene variation and protein structure prediction\u003c/h2\u003e\n \u003cp\u003ecBioPortal (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.cbioportal.org/\u003c/span\u003e\u003c/span\u003e) is an important public platform constructed by Memorial Sloan Kettering Cancer Center (MSK) (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e). Based on the TCGA database, the cBioPortal integrates data mining, integration, and visualization comprehensively. To show alteration frequency of \u003cem\u003eYAP1\u003c/em\u003e and to show mutations of \u003cem\u003eYAP1\u003c/em\u003e, \u0026ldquo;YAP1\u0026rdquo; was put in the search and it was submitted.\u003c/p\u003e\n \u003cp\u003eAlphaFold (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://alphafold.ebi.ac.uk/\u003c/span\u003e\u003c/span\u003e) can predict the unknown structures of proteins based on known structures (24, 25). AlphaFold\u0026rsquo;s website was accessed and \u0026ldquo;YAP1\u0026rdquo; was put in the search and it was submitted. \u003cem\u003eYAP1\u003c/em\u003e\u0026rsquo;s corresponding protein\u0026rsquo;s structure was shown, also the pathogenicity heatmap can be seen.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e2.4 Prediction of phosphorylation sites and protein interactions\u003c/h2\u003e\n \u003cp\u003ePhosphonet (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.phosphonet.ca\u003c/span\u003e\u003c/span\u003e) is a website that is adopted to predict and analyze phosphorylation sites of any protein. For further study of \u003cem\u003eYAP1\u003c/em\u003e\u0026rsquo;s phosphorylation site, Phosphonet\u0026rsquo;s website was opened. \u0026ldquo;YAP1\u0026rdquo; was put in the search and it was submitted.\u003c/p\u003e\n \u003cp\u003eString (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cn.string-db.org\u003c/span\u003e\u003c/span\u003e) is a website that analyzes Protein-Protein interaction (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e). To investigate the interaction between Yap1 and other proteins, String\u0026rsquo;s website was opened and \u0026ldquo;YAP1\u0026rdquo; was put in the search and it was submitted.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.1 YAP1\u0026rsquo;s expression was reduce in multiple cancers\u003c/h2\u003e\u003cp\u003e\u003cem\u003eYAP1\u003c/em\u003e is known to play a role in the development and progression of multiple cancers as a transcriptional regulator of this signaling pathway (\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). First of all, the patterns of \u003cem\u003eYAP1\u003c/em\u003e in cancer tissues were investigated by applying GEPIA. As exhibited, 31 pairs of cancers and their respective controls were studied, and the levels \u003cem\u003eYAP1\u003c/em\u003e in 17 types of cancer tissues were significantly lower than the controls, such as ACC (Adrenocortical carcinoma), BLCA (Bladder Urothelial Carcinoma), and UCEC (Uterine Corpus Endometrial Carcinoma), etc (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and B). In comparison, the expressions of \u003cem\u003eYAP1\u003c/em\u003e in DLBC (Lymphoid Neoplasm Diffuse Large B-cell Lymphoma), GBM (Glioblastoma multiforme) and PAAD (Pancreatic adenocarcinoma), etc. were significantly higher than the healthy controls.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAs shown in Timer2.0 results, among the 23 pairs of cancers and their respective controls, the mRNA expression patterns of \u003cem\u003eYAP1\u003c/em\u003e were significantly lower in 14 different types of cancers comparing to the normal controls. Additionally, 4 cancers exhibited significantly higher levels than their respective controls (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the remaining 10 tissues showed significantly lower levels than the normal controls (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) among these 23 pairs, such as BLCA, BRCA (Breast invasive carcinoma), CHOL (Cholangiocarcinoma), etc (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.2 YAP1 was widely expressed and nuclear-localized\u003c/h2\u003e\u003cp\u003eNext, the expression of \u003cem\u003eYAP1\u003c/em\u003e in normal organs, tissues and cells were also explored in the current investigation by employing HPA. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, YAP1 mRNA and protein patterns were evident and ubiquitously appeared, although there were variations between distinct tissues and organs. Both the mRNA and protein levels of YAP1 were high in muscle tissues, whereas the patterns were low in the eye.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe subcellular location of YAP1 in cultured cells were investigated by using HPA. As displayed in the Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, YAP1 was mainly located in the nuclei in U\u003csub\u003e2\u003c/sub\u003eOS cells.\u003c/p\u003e\u003cp\u003eFrom the pathological section of a 75 male patient who has lung cancer, it was clear that \u003cem\u003eYAP1\u003c/em\u003e was expressed in the cancer tissue (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). The staining level is medium and staining quantity\u0026thinsp;\u0026gt;\u0026thinsp;75%.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.3 YAP1\u0026rsquo;s survival analysis in PAAD and KIRS\u003c/h2\u003e\u003cp\u003eAs exhibited in the Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, PAAD and KIRS (Kidney renal clear cell carcinoma) were both statistically significant in GEPIA, HPA and KM plotter (P\u003csub\u003ePAAD\u003c/sub\u003e=0.005, 0.002, \u0026lt;\u0026thinsp;0.001; PKIRS\u0026thinsp;=\u0026thinsp;0.004, \u0026lt;\u0026thinsp;0.001, 0.028) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-F). Survival plots showed that \u003cem\u003eYAP1\u003c/em\u003e\u0026rsquo;s expression was poor prognostic indicator for PAAD, but favorable prognostic indicator for KIRS.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Expression correlated with immune infiltration\u003c/h2\u003e\u003cp\u003eAs it was shown in heat map, the expression of \u003cem\u003eYAP1\u003c/em\u003e had significant connections with T-cell CD4+\u0026rsquo;s immune infiltration for most of cancers, and most of connections were positive correlations, such as DLBC, ESCA (Esophageal carcinoma), GBM, etc (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB also shows that the expression of \u003cem\u003eYAP1\u003c/em\u003e has changed significant with infiltration level rise.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.5 YAP1 shows high alteration frequency in most of cancers\u003c/h2\u003e\u003cp\u003eAs it was shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA, many cancers showed alteration frequency of \u003cem\u003eYAP1\u003c/em\u003e. It was obvious that the most common alteration was Amplification, and Cervical squamous cell carcinoma had the highest alteration frequency (\u0026gt;\u0026thinsp;10%).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003ePhosphorylation plays critical roles in regulating gene expression. Therefore, various point mutations especially the variation of S276N may cause cancers (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.6 Many high-confidence phosphorylation sites were identified\u003c/h2\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, \u003cem\u003eYAP1\u003c/em\u003e had 33 phosphorylation sites, such as S21, S31, S61, etc.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eCompared the result in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB and Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, S61, T63, S94, S103, S105, T110, T114, T119, S127, S131, S138, T141, T143, T145, S149, T154, T156, S163, S164, S217, S236, S382 appeared to be phosphorylation site both in cBioportal and Phosphonet, these phosphorylation sites\u0026rsquo; chances to be YAP1\u0026rsquo;s phosphorylation sites were extremely high.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.7 Structure features and mutation indicated pathogenicity\u003c/h2\u003e\u003cp\u003eThe Yap1\u0026rsquo;s corresponding protein\u0026rsquo;s structure was shown (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eA\u003cb\u003e)\u003c/b\u003e. Many important part such as α-helix and β-pleated sheet had high confidence. As for the heatmap, it was obvious that many sites were pathogenic (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eB).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eCompared Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB and Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eB, and used high confidence sections in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eA, some of mutation sites, such as F95C, R262M and Q322K could be highly connected with cancers.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.8 Yap1 interacts with Hypoxic pathway-associated proteins\u003c/h2\u003e\u003cp\u003eAs exhibited in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e, Yap1 has some interacting protein, such as LATS1, LATS2, etc. LATS1 and LATS2 were both very important parts of Hippo signaling pathway-a hypoxic pathway. Different color lines meant Known Interactions, Predicted Interactions and others.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThere are several findings in this study: first, \u003cem\u003eYAP1\u003c/em\u003e is ubiquitously expressed in both normal tissues and disease tissues, and its level is lower in cancerous tissues; second, YAP1 is located in nuclei generally; third, the expression of \u003cem\u003eYAP1\u003c/em\u003e is significant correlated with immune infiltration of the immune cells in most types of tumors; fourth, expression of \u003cem\u003eYAP1\u003c/em\u003e is negatively and significantly associated with the survival of cancer patients largely; fifth, there are different variations of YAP1 in various cancers, and the R331W in YAP1 is observed in patients with cancer; furthermore, YAP1 structure is predicted and some pathogenetic points are revealed, which is associated with phosphorylation modification. In addition, the interacting proteins of LAST1/2 are the partners of YAP1. These data indicate that YAP1 is associated with cancers.\u003c/p\u003e\u003cp\u003eThe biggest novelty of this study is that YAP1 was correlated with various cancers, and some hotspots of YAP1 in cancers are predicted as pathogenetic points in tumors, indicating that it may serve as a possible biomarker in clinics.\u003c/p\u003e\u003cp\u003e\u003cem\u003eYAP1\u003c/em\u003e levels in cancerous tissues of colorectal cancers were higher than the controls(\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e), which is consistent with the findings of this study that \u003cem\u003eYAP1\u003c/em\u003e was higher than the respective controls in READ (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). The data in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB in the current investigation exhibit that Yap1 is expressed in the nuclei, which is further supported by previous studies that Yap1 is located in nuclei (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). The \u003cem\u003eYAP1\u003c/em\u003e\u0026rsquo;s expression level was negatively correlated with the immune infiltration of the CD\u003csup\u003e8\u003c/sup\u003e\u0026thinsp;+\u0026thinsp;T cells of the prostate cancer (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). In comparison, the pattern of YAP1 was significantly associated with the immune infiltration of the CD\u003csup\u003e4\u003c/sup\u003e\u0026thinsp;+\u0026thinsp;T cells in BRCA in the current investigation, suggesting these data were consistent with each other. The high levels of \u003cem\u003eYAP1\u003c/em\u003e were significant correlated with unfavorable overall survival in glioma patients (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), supporting the data in this study. R331W variation in YAP1 was discovered and confirmed in the patients with lung cancer (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e) (R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability), which was also validated in our study in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eThere are various limitations in this analysis of bioinformatics. First, there is only bioinformatic analysis, and there is little experimental data. Second, there is limited case numbers. Third, there are some conflicting data regarding the present investigation and previous investigations.\u003c/p\u003e\u003cp\u003eIn future, cell and animal studies should be done to validate the findings in this study. Furthermore, more cases should be recruited to further confirm the conclusion. Additionally, it should be made clear the conflicting conclusions.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eIn summary, \u003cem\u003eYAP1\u003c/em\u003e expressed differently across various cancers, with significantly reduced expression in multiple tissues compared to controls. It expressed widely among organs and primarily localized in the nucleus. In some specific cancers such as PAAD and KIRC, \u003cem\u003eYAP1\u003c/em\u003e\u0026rsquo;s expression level was associated with prognosis. Furthermore, \u003cem\u003eYAP1\u003c/em\u003e showed connections with immune cell infiltration. And genomic analysis indicated frequent alternations in \u003cem\u003eYAP1\u003c/em\u003e, and many mutation sites were located in high-confidence structural regions. Multiple phosphorylation sites were identified with high predictive confidence as well. Lastly, Yap1 was shown to interact with some key proteins involved in cancer signaling pathway. These findings provide a comprehensive overview of \u003cem\u003eYAP1\u003c/em\u003e\u0026rsquo;s expression, prognostic relevance, molecular characteristics, and interaction profile. Yap1 is significantly associated with pan-cancer, which may serve as a potential biomarker of cancers.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Informed Consent\u003c/strong\u003e\u003cbr\u003e The data used in this study were obtained from publicly available databases, which contain anonymized human data with no personally identifiable information. Therefore, no additional ethical approval or informed consent was required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003cbr\u003e Yufan Xu: Conceptualization, Investigation, Methodology, Software, Data curation, Formal analysis, Visualization, Writing - original draft, Writing - review \u0026amp; editing, Validation, Funding acquisition, Project administration, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003cbr\u003e The author declares no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr\u003e No specific funding was received for this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003cbr\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003cbr\u003e The author sincerely thanks the developers and curators of GEPIA, TIMER2.0, HPA, KM Plotter, cBioPortal, AlphaFold, PhosphoNet, and STRING databases for providing open access to their valuable data and analysis platforms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003cbr\u003e All data analyzed in this study were obtained from publicly available databases, including TIMER2.0 (http://timer.cistrome.org/), GEPIA (http://gepia.cancer-pku.cn/), KM plotter (https://kmplot.com), cBioPortal (https://www.cbioportal.org/), the Human Protein Atlas (https://www.proteinatlas.org/), AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/), PhosphoNet (https://www.phosphonet.ca/), and STRING (https://string-db.org/). The processed data and results that support the findings of this study are available within the manuscript. No new datasets were generated during the current study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63.\u003c/li\u003e\n \u003cli\u003eCrable J, Highfield MEF, Patmon F. Evidence-based practice knowledge, attitudes, practices, and barriers. Nursing. 2021;51(9):58-65.\u003c/li\u003e\n \u003cli\u003eZhang H, Ma Y, Zhang Q, Liu R, Luo H, Wang X. A pancancer analysis of the carcinogenic role of receptor-interacting serine/threonine protein kinase-2 (RIPK2) in human tumours. BMC Med Genomics. 2022;15(1):97.\u003c/li\u003e\n \u003cli\u003eNandini AS, Mustafa AB, Shushruta B, Tejaswini S, Harsha G, Jayshree A, et al. 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Nucleic Acids Res. 2017;45(D1):D362-d8.\u003c/li\u003e\n \u003cli\u003eSzklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447-52.\u003c/li\u003e\n \u003cli\u003eFranceschini A, Lin J, von Mering C, Jensen LJ. SVD-phy: improved prediction of protein functional associations through singular value decomposition of phylogenetic profiles. Bioinformatics. 2016;32(7):1085-7.\u003c/li\u003e\n \u003cli\u003eFranceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41(Database issue):D808-15.\u003c/li\u003e\n \u003cli\u003eSzklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, et al. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 2011;39(Database issue):D561-8.\u003c/li\u003e\n \u003cli\u003eJensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, et al. STRING 8--a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 2009;37(Database issue):D412-6.\u003c/li\u003e\n \u003cli\u003evon Mering C, Jensen LJ, Kuhn M, Chaffron S, Doerks T, Kr\u0026uuml;ger B, et al. STRING 7--recent developments in the integration and prediction of protein interactions. Nucleic Acids Res. 2007;35(Database issue):D358-62.\u003c/li\u003e\n \u003cli\u003evon Mering C, Jensen LJ, Snel B, Hooper SD, Krupp M, Foglierini M, et al. STRING: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res. 2005;33(Database issue):D433-7.\u003c/li\u003e\n \u003cli\u003evon Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. 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Scientific reports. 2020;10(1):8916.\u003c/li\u003e\n \u003cli\u003eStewart CA, Diao L, Xi Y, Wang R, Ramkumar K, Serrano AG, et al. YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities. Clin Cancer Res. 2024;30(20):4743-54.\u003c/li\u003e\n \u003cli\u003eDella Chiara G, Gervasoni F, Fakiola M, Godano C, D\u0026apos;Oria C, Azzolin L, et al. Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ. Nat Commun. 2021;12(1):2340.\u003c/li\u003e\n \u003cli\u003eSong H, Lu T, Han D, Zhang J, Gan L, Xu C, et al. YAP1 Inhibition Induces Phenotype Switching of Cancer-Associated Fibroblasts to Tumor Suppressive in Prostate Cancer. Cancer Res. 2024;84(22):3728-42.\u003c/li\u003e\n \u003cli\u003eWu Y, Hou Y, Xu P, Deng Y, Liu K, Wang M, et al. The prognostic value of YAP1 on clinical outcomes in human cancers. Aging (Albany NY). 2019;11(19):8681-700.\u003c/li\u003e\n \u003cli\u003eAhmed KY, Dadi AF, Ogbo FA, Page A, Agho KE, Akalu TY, et al. Population-Modifiable Risk Factors Associated With Childhood Stunting in Sub-Saharan Africa. JAMA Network Open. 2023;6(10):e2338321-e.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"YAP1, pan-cancer, survival time, biomarker, immune infiltration","lastPublishedDoi":"10.21203/rs.3.rs-6883851/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6883851/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackgrounds and aims:\u003c/h2\u003e\u003cp\u003eCancers threaten health and life of patients with tumors. It is important to diagnose and treat various tumors as early as possible. However, there is limited early biomarkers for cancers. Yes-associated protein 1 (Yap1) is involved in the Hippo signaling pathway, and thus regulating development and cell growth. Yap1\u0026rsquo;s role in pan-cancer remains to be investigated. The objective of the present investigation was to explore the possible role and mechanism of Yap1 in pan-cancer.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eTimer2.0 and GEPIA were employed to analyze the expression of \u003cem\u003eYAP1\u003c/em\u003e in cancerous tissues and controls; HPA was used to study the expression of \u003cem\u003eYAP1\u003c/em\u003e in different tissues and subcellular location; for survival analysis, GEPIA, the HPA, and KM plotter were utilized to generate survival curves, evaluating the prognostic significance of \u003cem\u003eYAP1\u003c/em\u003e expression; cBioPortal was used to investigate the mutation frequency and genetic alterations of \u003cem\u003eYAP1\u003c/em\u003e; AlphaFold was applied to predict the structure of Yap1 and identify potential pathogenic sites, while PhosphoNet helped in predicting and analyzing phosphorylation sites of Yap1; the STRING was employed to explore Yap1's interacting proteins.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe levels of \u003cem\u003eYAP1\u003c/em\u003e in tumor tissues were mostly lower than controls; Yap1 was ubiquitously expressed and located in cytosol; \u003cem\u003eYAP1\u003c/em\u003e is a significant predictor of survival in PAAD and KIRC; its expression is closely linked to immune infiltration; \u003cem\u003eYAP1\u003c/em\u003e exhibits a high mutation frequency across various cancer types; many phosphorylation sites especially S276 in Yap1 is highly a phosphorylation site; Yap1 interacts with proteins including Last1 and Last2 associated with the hypoxia pathway.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eYap1 is significantly associated with pan-cancer, which may serve as a potential biomarker of cancers.\u003c/p\u003e","manuscriptTitle":"Role and mechanism of YAP1 in pan-cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 13:06:55","doi":"10.21203/rs.3.rs-6883851/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cfda1ee5-5234-4ef2-a28d-a3f389f1473a","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51497647,"name":"Health sciences/Oncology/Cancer/Cancer genetics"},{"id":51497648,"name":"Health sciences/Oncology/Cancer/Cancer genomics"},{"id":51497649,"name":"Health sciences/Oncology/Cancer/Cancer therapy"},{"id":51497650,"name":"Health sciences/Oncology/Cancer/Tumour biomarkers"},{"id":51497651,"name":"Health sciences/Oncology/Cancer/Tumour immunology"},{"id":51497652,"name":"Health sciences/Oncology/Cancer"}],"tags":[],"updatedAt":"2026-02-07T10:30:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 13:06:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6883851","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6883851","identity":"rs-6883851","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}