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Yes-Associated Protein Up-regulates Jagged-1 and Activates the NOTCH Pathway in Human Hepatocellular Carcinoma
Open accessAbstract
Background & aims Cancer cells often lose contact inhibition to undergo anchorage-independent proliferation and become resistant to apoptosis by inactivating the Hippo signaling pathway, resulting in activation of the transcriptional co-activator yes-associated protein (YAP). However, the oncogenic mechanisms of YAP activity are unclear.Methods By using cross-species analysis of expression data, the Notch ligand Jagged-1 (Jag-1) was identified as a downstream target of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells. We analyzed the functions of YAP in HCC cells via overexpression and RNA silencing experiments. We used transgenic mice that overexpressed a constitutively activated form of YAP (YAP(S127A)), and measured protein levels in HCC, colorectal and pancreatic tumor samples from patients.Results Human HCC cell lines and mouse hepatocytes that overexpress YAP(S127A) up-regulated Jag-1, leading to activation of the Notch pathway and increased proliferation. Induction of Jag-1, activation of Notch, and cell proliferation required binding of YAP to its transcriptional partner TEA domain family member 4 (TEAD4); TEAD4 binding required the Mst1/2 but not β-catenin signaling. Levels of YAP correlated with Jag-1 expression and Notch signaling in human tumor samples and correlated with shorter survival times of patients with HCC or colorectal cancer.Conclusions The transcriptional regulator YAP up-regulates Jag-1 to activate Notch signaling in HCC cells and mouse hepatocytes. YAP-dependent activity of Jag-1 and Notch correlate in human HCC and colorectal tumor samples with patient survival times, suggesting the use of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer. Transcript profiling: microarray information was deposited at the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jxepvsumwosqkve&acc=GSE35004).
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“Despite the protective effects of IL-6, YAP-mediated Notch signaling activation contributed to tumor growth in human hepatocellular carcinoma and murine hepatocytes (Tschaharganeh et al., 2013”
From Targeting Interleukin-6 Signaling in Clinic (2019) · cites this paper as Tschaharganeh et al., 2013
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“Over the years, a number of inhibitors targeting YAP/TAZ-TEAD have been reported, including peptides such as super-TDU (173),437 and small molecules such as verteporfin (174) and MGH-CP1 (175).438–440”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [439]
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InfluentialTEAD mediates YAP-dependent gene induction and growth control
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“preventing it from activating TEA domain family member (TEAD)-mediated transcription of connective tissue growth factor (CTGF) (9), secreted phosphoprotein 1 (SPP1) (10), transforming growth factor beta (TGFβ) (11), and Jagged 1 (JAG1) (12).”
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“There is strong evidence that the Notch pathway is activated by YAP through direct transcriptional targeting of JAG1 in the liver (27, 50).”
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“Additionally, it has recently been demonstrated that YAP activates the Notch pathway by up-regulating jagged 1 in human hepatocellular carcinoma.(27) To further elucidate whether these tumors recapitulate these human phenotypes, Notch and IL-6 pathways were investigated.”
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“In hepatocellular carcinomas, YAP1 up-regulates Jagged-1 and stimulates Notch signaling in a non-cell autonomous manner [163].”
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“YAP directly regulates the expression of key factors that promote biliary epithelial development, including Sox9((36)) and components of the notch signaling pathway.((27,28)) Indeed, when YAP is activated by LATS1/2 depletion, we observed an increase in the number of HNF4a/Sox9 double- positive cells and an increase i…”
BackgroundYu, W., Qiao, Y., Tang, X., Ma, L., Wang, Y., Zhang, X., Weng, W., Pan, Q., Yu, Y., Sun, F., et al. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.09.011 · Cited by 102
Differential effects of targeting Notch receptors in a mouse model of liver cancer
Huntzicker, E. G., Hötzel, K., Choy, L., Che, L., Ross, J., Pau, G., Sharma, N., Siebel, C. W., Chen, X., & French, D. M. (2014) · Hepatology · doi:10.1002/hep.27566 · Cited by 102
“Although multiple studies have attempted to determine the expression pattern of Notch1 in human HCC samples, the results have thus far been inconsistent and controversial, from membrane or cytoplasm staining in 50% of HCC samples(20) with no nuclear localization of Notch1 in HCCs to nuclear staining of Notch1 in 49% o…”
BackgroundSelf-citationHippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest
Manderfield, L. J., Aghajanian, H. K., Engleka, K. A., Lim, L. Y., Lui, F., Jain, R., Li, L., Olson, E. N., & Epstein, J. A. (2015) · Development · doi:10.1242/dev.125807 · Cited by 100
Inflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies
Lee, Y. A., & Friedman, S. L. (2021) · Journal of Internal Medicine · doi:10.1111/joim.13380 · Cited by 104
Hippo‐YAP signaling pathway: A new paradigm for cancer therapy
Ma, Y., Yang, Y., Wang, F., Wei, Q., & Qin, H. (2014) · International Journal of Cancer · doi:10.1002/ijc.29073 · Cited by 100
“A higher expression of YAP correlated with Jag-1 expression and Notch signaling in tumor samples and with shorter survival times of patients with HCC or colorectal cancer, indicating the utility of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer.(62) The roles of miRNA and lncRNA in tumorigenesis…”
BackgroundNovel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation
Grampa, V., Delous, M., Zaidan, M., Odye, G., Thomas, S., Elkhartoufi, N., Filhol-Blin, E., Niel, O., Silbermann, F., Lebreton, C., et al. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1005894 · Cited by 94
Proliferative polyploid cells give rise to tumors via ploidy reduction
Matsumoto, T., Wakefield, L., Peters, A. M., Peto, M., Spellman, P. T., & Grompe, M. (2021) · Nature Communications · doi:10.1038/s41467-021-20916-y · Cited by 101
The oncogenic role of Jagged1/Notch signaling in cancer
Xiu, M., Liu, Y., & Kuang, B. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110416 · Cited by 93
YAP and TAZ Take Center Stage in Cancer
Zhang, K., Qi, H.-X., Hu, Z., Chang, Y., Shi, Z., Han, X., Han, Y., Zhang, R., Zhang, Z., Chen, T., et al. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b01014 · Cited by 94
de Lima, J. E., Bonnin, M.-A., Birchmeier, C., & Duprez, D. (2016) · eLife · doi:10.7554/elife.15593 · Cited by 89
“Oncogenic YAP variants activate the NOTCH ligand JAG1 and consequently NOTCH signaling in hepatocellular carcinoma cells (Tschaharganeh et al., 2013).”
BackgroundThe Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors
Hagenbeek, T., Webster, J., Kljavin, N. M., Chang, M. T., Pham, T., Lee, H.-J., Klijn, C., Cai, A. G., Totpal, K., Ravishankar, B., et al. (2018) · Science Signaling · doi:10.1126/scisignal.aaj1757 · Cited by 85
A cell-surface β-hydroxylase is a biomarker and therapeutic target for hepatocellular carcinoma
Aihara, A., Huang, C.-K., Olsen, M. J., Lin, Q., Chung, W., Tang, Q., Dong, X., & Wands, J. R. (2014) · Hepatology · doi:10.1002/hep.27275 · Cited by 88
Emerging role of Hippo pathway in gastric and other gastrointestinal cancers
Kang, W. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i3.1279 · Cited by 86
The Hippo signaling pathway provides novel anti-cancer drug targets
Bae, J. S., Kim, S. M., & Lee, H. (2016) · Oncotarget · doi:10.18632/oncotarget.14306 · Cited by 88
“A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency.”
BackgroundLiver Inflammation and Hepatobiliary Cancers
Leone, V., Ali, A., Weber, A., Tschaharganeh, D. F., & Heikenwälder, M. F. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.01.012 · Cited by 88
Self-citationZhang, X., Liu, X., Luo, J., Xiao, W. L., Ye, X., Chen, M., Li, Y., & Zhang, G.-J. (2016) · Oncogenesis · doi:10.1038/oncsis.2016.67 · Cited by 84
Shome, D., von Woedtke, T., Riedel, K., & Masur, K. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/4910280 · Cited by 85
Molecular Pathways: Hippo Signaling, a Critical Tumor Suppressor
Sebio, A., & Lenz, H. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0411 · Cited by 81
“The expression of the Notch ligand Jagged-1 is upregulated by nuclear YAP in colorectal and hepatocarcinoma tissue samples and correlates with the patient survival (28).”
BackgroundWatanabe, Y., Miyasaka, K. Y., Kubo, A., Kida, Y. S., Nakagawa, O., Hirate, Y., Sasaki, H., & Ogura, T. (2017) · Scientific Reports · doi:10.1038/srep46135 · Cited by 80
Regulation of the Hippo pathway in cancer biology
Moon, S., Park, S. Y., & Park, H. W. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2804-1 · Cited by 77
Hippo Signaling in the Liver – A Long and Ever-Expanding Story
Manmadhan, S., & Ehmer, U. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00033 · Cited by 80
“In contrast, Wnt signaling has been shown to inhibit hepatic YAP/TAZ signaling – in part by interfering with the NotchYAP feedback loop (Tschaharganeh et al., 2013; Kim et al., 2017b,c).”
The history and regulatory mechanism of the Hippo pathway
Kim, W., & Jho, E. (2018) · BMB Reports · doi:10.5483/bmbrep.2018.51.3.022 · Cited by 81
“positive feedback loop during tumorigenesis (120, 134, 138).”
BackgroundYAP1 enhances cell proliferation, migration, and invasion of gastric cancer in vitro and in vivo
Sun, D., Li, X.-T., He, Y., Li, W., Wang, Y., Wang, H., Jiang, S., & Xin, Y. (2016) · Oncotarget · doi:10.18632/oncotarget.13188 · Cited by 76
“Furthermore, YAP1 (located on 11q22) has been identified as a candidate oncogene in several cancers; its overexpression and increased nuclear localization have been reported in breast cancer [8], hepatocellular carcinoma [10], colorectal cancer [11], GC [12], pancreatic cancer [13], and esophageal squamous cell carcin…”
BackgroundWei, T., Weiler, S. M. E., Tóth, M., Sticht, C., Lutz, T., Thomann, S., Torre, C. D. L., Straub, B. K., Merker, S., Ruppert, T., et al. (2019) · Oncogene · doi:10.1038/s41388-019-0801-y · Cited by 76
Self-citationFerguson, G. B., & Martínez-Agosto, J. A. (2014) · Current Biology · doi:10.1016/j.cub.2014.09.081 · Cited by 76
Li, M., Lu, J., Zhang, F., Li, H., Zhang, B., Wu, X., Tan, Z., Zhang, L., Gao, G., Mu, J., et al. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.08.036 · Cited by 74
Recent Advances of the Hippo/YAP Signaling Pathway in Brain Development and Glioma
Ouyang, T., Meng, W., Li, M., Hong, T., & Zhang, N. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00762-9 · Cited by 74
Ren, K., Li, T., Zhang, W., Ren, J., Li, Z., & Wu, G. (2016) · Journal of Biomedical Science · doi:10.1186/s12929-016-0295-7 · Cited by 72
The Ambivalent Function of YAP in Apoptosis and Cancer
Zhang, X., Abdelrahman, A., Vollmar, B., & Zechner, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123770 · Cited by 71
“Decreased Increased 27307755 [32] Lung shRNA 25665005 [33] Breast shRNA 28892790 [18] Stomach siRNA 27073556 [34] Stomach siRNA 21805037 [35] Liver siRNA 23419361 [36] Liver siRNA 27323827 [37] Liver siRNA 29928445 [38] Pancreas siRNA 27738325 [39] Pancreas siRNA 27669292 [40] Pancreas siRNA 22396793 [41] Colon/Rectum…”
BackgroundHepatic Hippo signaling inhibits development of hepatocellular carcinoma
Liu, Y., Wang, X., & Yang, Y. (2020) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2020.0178 · Cited by 75
“In human HCC, a Notch ligand JAGGED 1 (JAG 1) has been identified as a direct YAP downstream target contributes to high Notch signaling activity in tumor.(65) In mice, Notch ligand JAG 1 and Notch receptor Notch2 have been also identified as downstream targets of YAP.”
BackgroundLiu, M., Yan, Q., Sun, Y. J., Nam, Y., Hu, L., Loong, J. H. C., Ouyang, Q., Zhang, Y., Li, H., Kong, F.-E., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1912146117 · Cited by 66
Self-citationLi, X., Tao, J., Cigliano, A., Sini, M., Caldéraro, J., Azoulay, D., Wang, C., Liu, Y., Jiang, L., Evert, K., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3546 · Cited by 65
Self-citationTGF-β1 and TGF-β2 abundance in liver diseases of mice and men
Dropmann, A., Dediulia, T., Breitkopf‐Heinlein, K., Korhonen, H., Janicot, M., Weber, S. N., Thomas, M., Piiper, A., Bertrán, E., Fabregat, I., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6967 · Cited by 69
“uncovered a universal organ size control mechanism in metazoan, showing that Yap overexpression in the liver increased liver mass in transgenic mice extensively and strongly induced TGF-β2 expression [51, 52].”
BackgroundA Novel Notch–YAP Circuit Drives Stemness and Tumorigenesis in Embryonal Rhabdomyosarcoma
Slemmons, K. K., Crose, L. E. S., Riedel, S., Sushnitha, M., Belyea, B., & Linardic, C. M. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0004 · Cited by 62
“For example, in neural stem cells Notch transcriptionally regulates YAP (27), while in intestinal stem cells (28, 29), adult hepatocytes (30), colon cancer cells (29), and hepatocellular carcinoma (31), YAP activates Notch.”
BackgroundThe roles of signaling pathways in liver repair and regeneration
Valizadeh, A., Majidinia, M., Kafil, H. S., Yousefi, M., & Yousefi, B. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28336 · Cited by 63
“Some genes (such as connective tissue growth factor, JAG1, and Notch‐2, which direct hippo signaling targets; Tschaharganeh et al., 2013) are cardinal for nuclear localization of YAP and TAZ for liver growth and regeneration (Zhao & Ye, 2008) In this regard, transgenic over- expression of YAP in…”
Roles of the H ippo pathway in lung development and tumorigenesis
Yeung, B., Yu, J., & Yang, X. (2015) · International Journal of Cancer · doi:10.1002/ijc.29457 · Cited by 65
“In addition, TAZ/YAP may activate different downstream targets in different cell types (57, 70-73).”
BackgroundWang, J., Tang, X., Weng, W., Qiao, Y., Lin, J., Liu, W., Liu, R., Ma, L., Yu, W., Yu, Y., et al. (2015) · Oncogene · doi:10.1038/onc.2015.36 · Cited by 62
Metadata
- Authors
- Tschaharganeh, D. F., Chen, X., Latzko, P., Malz, M., Gaida, M. M., Felix, K., Ladu, S., Singer, S., Pinna, F., Gretz, N., Sticht, C., Tomasi, M. L., Delogu, S., Evert, M., Fan, B., Ribback, S., Jiang, L., Brozzetti, S., Bergmann, F., Dombrowski, F., Schirmacher, P., Calvisi, D. F., & Breuhahn, K.
- Affiliations
- University Hospital Heidelberg (DE)
- University of California, San Francisco (US)
- University of Chieti-Pescara (IT)
- Medizinische Fakultät Mannheim (DE)
- University of Southern California (US)
- Universität Greifswald (DE)
- Sapienza University of Rome (IT)
- Corresponding author
- Breuhahn, Kai
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 144
- Issue
- 7
- Pages
- 1530-1542.e12
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC3665638
- OpenAlex
- W2060323466
- Cited by
- 326
- References
- 47
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 16 · 2023: 19 · 2022: 26 · 2021: 29 · 2020: 35 · 2019: 26 · 2018: 26 · 2017: 25 · 2016: 28 · 2015: 35 · 2014: 28 · 2013: 8
- FWCI
- 19.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- YAP, Jagged1, Notch signaling, hepatocellular carcinoma, TEAD4, MST1/2, Hippo signaling pathway, colorectal cancer, pancreatic cancer, cell proliferation, patient survival, transcriptional coactivator, therapeutic target
- MeSH terms
- Serrate-Jagged Proteins, Jagged-1 Protein, YAP-Signaling Proteins, TEA Domain Transcription Factors, Animals, Calcium-Binding Proteins, DNA-Binding Proteins, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Membrane Proteins, Muscle Proteins, Phosphoproteins, Transcription Factors, Up-Regulation, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, Hepatocytes, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Receptors, Notch
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