Abstract
The Hippo signalling pathway has emerged as a major player in many aspects of liver biology, such as development, cell fate determination, homeostatic function and regeneration from injury. The regulation of Hippo signalling is complex, with activation of the pathway by diverse upstream inputs including signals from cellular adhesion, mechanotransduction and crosstalk with other signalling pathways. Pathological activation of the downstream transcriptional co-activators yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, encoded by WWTR1), which are negatively regulated by Hippo signalling, has been implicated in multiple aspects of chronic liver disease, such as the development of liver fibrosis and tumorigenesis. Thus, development of pharmacological inhibitors of YAP–TAZ signalling has been an area of great interest. In this Review, we summarize the diverse roles of Hippo signalling in liver biology and highlight areas where outstanding questions remain to be investigated. Greater understanding of the mechanisms of Hippo signalling in liver function should help facilitate the development of novel therapies for the treatment of liver disease.
Key points
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During embryonic liver development, yes-associated protein 1 (YAP) activity in hepatoblasts suppresses hepatocyte differentiation and is essential for proper cholangiocyte maturation and formation of the intrahepatic biliary network.
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During adult liver homeostasis, YAP activity is largely dispensable in hepatocytes but is required for the maintenance of mature cholangiocytes through its protective effects against exposure to hydrophobic bile acids.
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YAP is an important regulator of liver cell fate owing to its ability to promote hepatocyte-to-cholangiocyte transdifferentiation, and its activity in cholangiocytes drives the ductular reaction during chronic liver injury.
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YAP–transcriptional co-activator with PDZ-binding motif (TAZ) activity in hepatocytes, hepatic stellate cells, Kupffer cells and liver sinusoidal endothelial cells promotes inflammation and fibrosis in multiple models of nonalcoholic steatohepatitis and chemical-induced liver fibrosis.
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YAP is a potent oncogene and high YAP activity is frequently observed in hepatocellular carcinoma, hepatoblastoma and cholangiocarcinoma, where it promotes tumour cell proliferation, drug resistance and potentially immune evasion.
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Pharmacological targeting of YAP–TAZ holds great potential, either through inhibition of YAP–TAZ activity for anti-cancer or anti-fibrotic therapies or through promotion of YAP–TAZ activity to enhance liver regeneration.
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References
Asrani, S. K., Devarbhavi, H., Eaton, J. & Kamath, P. S. Burden of liver diseases in the world. J. Hepatol. 70, 151–171 (2019).
Michalopoulos, G. K. & DeFrances, M. C. Liver regeneration. Science 276, 60–66 (1997).
Pellicoro, A., Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 14, 181–194 (2014).
Wu, S., Huang, J., Dong, J. & Pan, D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445–456 (2003).
Harvey, K. F., Pfleger, C. M. & Hariharan, I. K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457–467 (2003).
Dong, J. et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007).
Camargo, F. D. et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 17, 2054–2060 (2007).
Creasy, C. L. & Chernoff, J. Cloning and characterization of a member of the MST subfamily of Ste20-like kinases. Gene 167, 303–306 (1995).
Creasy, C. L., Ambrose, D. M. & Chernoff, J. The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain. J. Biol. Chem. 271, 21049–21053 (1996).
Tapon, N. et al. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467–478 (2002).
Tao, W. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat. Genet. 21, 177–181 (1999).
Yin, F. et al. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 154, 1342–1355 (2013).
Cooper, J. & Giancotti, F. G. Molecular insights into NF2/Merlin tumor suppressor function. FEBS Lett. 588, 2743–2752 (2014).
Huang, J., Wu, S., Barrera, J., Matthews, K. & Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122, 421–434 (2005).
Zhao, B., Li, L., Tumaneng, K., Wang, C. Y. & Guan, K. L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(β-TRCP). Genes Dev. 24, 72–85 (2010).
Kanai, F. et al. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 19, 6778–6791 (2000).
Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007).
Zhao, B. et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 22, 1962–1971 (2008).
Yagi, R., Chen, L. F., Shigesada, K., Murakami, Y. & Ito, Y. A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 18, 2551–2562 (1999).
Varelas, X. et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev. Cell 19, 831–844 (2010).
Schlegelmilch, K. et al. Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell 144, 782–795 (2011).
Cordenonsi, M. et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147, 759–772 (2011).
Mohseni, M. et al. A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat. Cell Biol. 16, 108–117 (2014).
Nguyen, H. B., Babcock, J. T., Wells, C. D. & Quilliam, L. A. LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap. Oncogene 32, 4100–4109 (2013).
Herr, K. J. et al. Loss of α-catenin elicits a cholestatic response and impairs liver regeneration. Sci. Rep. 4, 6835 (2014).
Kim, N. G., Koh, E., Chen, X. & Gumbiner, B. M. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc. Natl Acad. Sci. USA 108, 11930–11935 (2011).
Benham-Pyle, B. W., Pruitt, B. L. & Nelson, W. J. Cell adhesion. Mechanical strain induces E-cadherin-dependent Yap1 and β-catenin activation to drive cell cycle entry. Science 348, 1024–1027 (2015).
Bai, H. et al. Yes-associated protein impacts adherens junction assembly through regulating actin cytoskeleton organization. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G396–G411 (2016).
Sun, S. & Irvine, K. D. Cellular organization and cytoskeletal regulation of the hippo signaling network. Trends Cell Biol. 26, 694–704 (2016).
Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).
Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).
Zhao, B. et al. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 26, 54–68 (2012).
Wada, K., Itoga, K., Okano, T., Yonemura, S. & Sasaki, H. Hippo pathway regulation by cell morphology and stress fibers. Development 138, 3907–3914 (2011).
Sun, P. et al. Maintenance of primary hepatocyte functions in vitro by inhibiting mechanical tension-induced YAP activation. Cell Rep. 29, 3212–3222.e4 (2019).
Zhao, B. et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes. Dev. 25, 51–63 (2011).
Chan, S. W. et al. Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J. Biol. Chem. 286, 7018–7026 (2011).
Moroishi, T. et al. A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 29, 1271–1284 (2015).
Mana-Capelli, S., Paramasivam, M., Dutta, S. & McCollum, D. Angiomotins link F-actin architecture to Hippo pathway signaling. Mol. Biol. Cell 25, 1676–1685 (2014).
Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010).
Yi, C. et al. The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis. Sci. Signal. 6, ra77 (2013).
Mao, B., Gao, Y., Bai, Y. & Yuan, Z. Hippo signaling in stress response and homeostasis maintenance. Acta Biochim. Biophys. Sin. 47, 2–9 (2015).
Koo, J. H. & Guan, K. L. Interplay between YAP/TAZ and metabolism. Cell Metab. 28, 196–206 (2018).
Yu, F. X. et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780–791 (2012).
Park, H. W. et al. Alternative Wnt signaling activates YAP/TAZ. Cell 162, 780–794 (2015).
Mo, J. S., Yu, F. X., Gong, R., Brown, J. H. & Guan, K. L. Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes Dev. 26, 2138–2143 (2012).
Reddy, B. V. & Irvine, K. D. Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev. Cell 24, 459–471 (2013).
Rizvi, S. et al. A hippo and fibroblast growth factor receptor autocrine pathway in cholangiocarcinoma. J. Biol. Chem. 291, 8031–8047 (2016).
Straßburger, K., Tiebe, M., Pinna, F., Breuhahn, K. & Teleman, A. A. Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP. Dev. Biol. 367, 187–196 (2012).
Li, P. et al. αE-catenin inhibits a Src-YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway. Genes Dev. 30, 798–811 (2016).
Si, Y. et al. Src inhibits the hippo tumor suppressor pathway through tyrosine phosphorylation of Lats1. Cancer Res. 77, 4868–4880 (2017).
Hong, A. W. et al. Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP. EMBO Rep. 18, 72–86 (2017).
Moon, S. et al. Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization. EMBO Rep. 18, 61–71 (2017).
Oudhoff, M. J. et al. Control of the hippo pathway by Set7-dependent methylation of Yap. Dev. Cell 26, 188–194 (2013).
Fang, L. et al. SET1A-mediated mono-methylation at K342 regulates YAP activation by blocking its nuclear export and promotes tumorigenesis. Cancer Cell 34, 103–118.e9 (2018).
Jiang, Y. et al. Pregnane X receptor regulates liver size and liver cell fate by yes-associated protein activation in mice. Hepatology 69, 343–358 (2019).
Anakk, S. et al. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep. 5, 1060–1069 (2013).
Kuroda, S. et al. Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin-mediated cell–cell adhesion. Science 281, 832–835 (1998).
Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014).
Lee, D. H. et al. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nat. Commun. 7, 11961 (2016).
Yuan, W. C. et al. NUAK2 is a critical YAP target in liver cancer. Nat. Commun. 9, 4834 (2018).
Wang, X. et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab. 24, 848–862 (2016).
Liu, P. et al. Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development. Oncotarget 8, 73433–73447 (2017).
Cox, A. G. et al. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat. Cell Biol. 18, 886–896 (2016).
Jeong, S. H. et al. Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. J. Clin. Invest. 128, 1010–1025 (2018).
Lemaigre, F. P. Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology 137, 62–79 (2009).
Gordillo, M., Evans, T. & Gouon-Evans, V. Orchestrating liver development. Development 142, 2094–2108 (2015).
Kyrmizi, I. et al. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev. 20, 2293–2305 (2006).
Yang, L. et al. A single-cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation. Hepatology 66, 1387–1401 (2017).
Alder, O. et al. Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation. Cell Rep. 9, 261–271 (2014).
Yi, J. et al. Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ. Hepatology 64, 1757–1772 (2016).
Song, H. et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc. Natl Acad. Sci. USA 107, 1431–1436 (2010).
Lee, K. P. et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 8248–8253 (2010).
Wu, N. et al. The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. Lab. Invest. 97, 843–853 (2017).
Molina, L. M. et al. Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors. Cell Rep. 36, 109310 (2021).
Verboven, E. et al. Regeneration defects in yap and taz mutant mouse livers are caused by bile duct disruption and cholestasis. Gastroenterology 160, 847–862 (2021).
Lu, L., Finegold, M. J. & Johnson, R. L. Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Exp. Mol. Med. 50, e423 (2018).
Fitamant, J. et al. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression. Cell Rep. 10, 1692–1707 (2015).
Bai, H. et al. Yes-associated protein regulates the hepatic response after bile duct ligation. Hepatology 56, 1097–1107 (2012).
Pepe-Mooney, B. J. et al. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell 25, 23–38.e8 (2019).
Pocaterra, A. et al. F-actin dynamics regulates mammalian organ growth and cell fate maintenance. J. Hepatol. 71, 130–142 (2019).
Schaub, J. R., Malato, Y., Gormond, C. & Willenbring, H. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep. 8, 933–939 (2014).
Yanger, K. et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 15, 340–349 (2014).
Planas-Paz, L. et al. YAP, but Not RSPO-LGR4/5, signaling in biliary epithelial cells promotes a ductular reaction in response to liver injury. Cell Stem Cell 25, 39–53.e10 (2019).
Russell, J. O. et al. Hepatocyte-specific β-catenin deletion during severe liver injury provokes cholangiocytes to differentiate into hepatocytes. Hepatology 69, 742–759 (2019).
Deng, X. et al. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23, 114–122.e3 (2018).
Raven, A. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547, 350–354 (2017).
Choi, T. Y., Ninov, N., Stainier, D. Y. & Shin, D. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 146, 776–788 (2014).
Schaub, J. R. et al. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature 557, 247–251 (2018).
Michalopoulos, G. K., Barua, L. & Bowen, W. C. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41, 535–544 (2005).
Wu, H. et al. The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense. Cell Rep. 3, 1663–1677 (2013).
Fan, F. et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci. Transl. Med. 8, 352ra108 (2016).
Poudel, S. et al. Hepatocyte specific deletion of Yes-associated protein (YAP) improves recovery from acetaminophen-induced acute liver injury. Toxicol. Sci. 184, 276–285 (2021).
Loforese, G. et al. Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2. EMBO Mol. Med. 9, 46–60 (2017).
Swiderska-Syn, M. et al. Hedgehog regulates Yes-associated protein 1 in regenerating mouse liver. Hepatology 64, 232–244 (2016).
Paranjpe, S. et al. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 64, 1711–1724 (2016).
Ko, S., Russell, J. O., Molina, L. M. & Monga, S. P. Liver progenitors and adult cell plasticity in hepatic injury and repair: knowns and unknowns. Annu. Rev. Pathol. 15, 23–50 (2020).
Bangru, S. et al. Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration. Nat. Struct. Mol. Biol. 25, 928–939 (2018).
Li, W. et al. A homeostatic arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling. Cell Stem Cell 25, 54–68.e55 (2019).
Chang, L. et al. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 563, 265–269 (2018).
Mooring, M. et al. Hepatocyte stress increases expression of Yes-associated protein and transcriptional coactivator with PDZ-binding motif in hepatocytes to promote parenchymal inflammation and fibrosis. Hepatology 71, 1813–1830 (2020).
Liu, Y. et al. Activation of YAP attenuates hepatic damage and fibrosis in liver ischemia–reperfusion injury. J. Hepatol. 71, 719–730 (2019).
Mannaerts, I. et al. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. J. Hepatol. 63, 679–688 (2015).
Martin, K. et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat. Commun. 7, 12502 (2016).
Song, K. et al. Yes-associated protein in Kupffer cells enhances the production of proinflammatory cytokines and promotes the development of nonalcoholic steatohepatitis. Hepatology 72, 72–87 (2020).
Qing, J. et al. Dopamine receptor D2 antagonization normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis. J. Hepatol. https://doi.org/10.1016/j.jhep.2021.09.032 (2021).
Nakajima, H. et al. Flow-dependent endothelial YAP regulation contributes to vessel maintenance. Dev. Cell 40, 523–536.e6 (2017).
Zhang, C. et al. Oroxylin A prevents angiogenesis of LSECs in liver fibrosis via inhibition of YAP/HIF-1α signaling. J. Cell Biochem. 119, 2258–2268 (2018).
Zhou, D. et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425–438 (2009).
Lu, L. et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl Acad. Sci. USA 107, 1437–1442 (2010).
Tschaharganeh, D. F. et al. Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 144, 1530–1542.e12 (2013).
Li, H. et al. Deregulation of Hippo kinase signalling in human hepatic malignancies. Liver Int. 32, 38–47 (2012).
Xu, M. Z. et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 115, 4576–4585 (2009).
Sohn, B. H. et al. Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma. Clin. Cancer Res. 22, 1256–1264 (2016).
Wang, Y. et al. Comprehensive molecular characterization of the hippo signaling pathway in cancer. Cell Rep. 25, 1304–1317.e5 (2018).
Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006).
Kim, I. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28, 940–946 (2007).
Yang, F. et al. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 67, 863–867 (2007).
Liu, Q. et al. Glycogen accumulation and phase separation drives liver tumor initiation. Cell 184, 5559–5576.e19 (2021).
Xia, H. et al. EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy. Cell Death Dis. 9, 269 (2018).
Chakraborty, S. et al. Agrin as a mechanotransduction signal regulating YAP through the hippo pathway. Cell Rep. 18, 2464–2479 (2017).
Gao, J. et al. Cirrhotic stiffness affects the migration of hepatocellular carcinoma cells and induces sorafenib resistance through YAP. J. Cell Physiol. 234, 2639–2648 (2019).
Liang, Y. et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology 57, 1847–1857 (2013).
Ma, B. et al. Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nat. Cell Biol. 17, 95–103 (2015).
Zhou, T. Y. et al. Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance to sorafenib in hepatocellular carcinoma cells. Sci. Rep. 6, 30483 (2016).
Cho, K. et al. YAP/TAZ suppress drug penetration into hepatocellular carcinoma through stromal activation. Hepatology 74, 2605–2621 (2021).
Kim, W. et al. Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis. J. Clin. Invest. 127, 137–152 (2017).
Tao, J. et al. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 147, 690–701 (2014).
Park, Y. Y. et al. Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma. Hepatology 63, 159–172 (2016).
Smith, J. L. et al. YAP1 withdrawal in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells. Hepatology 73, 1011–1027 (2021).
Pei, T. et al. YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 6, 17206–17220 (2015).
Marti, P. et al. YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors. Hepatology 62, 1497–1510 (2015).
Wu, H. et al. Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma. Tumour Biol. 37, 13499–13508 (2016).
Rizvi, S. et al. YAP-associated chromosomal instability and cholangiocarcinoma in mice. Oncotarget 9, 5892–5905 (2018).
Fan, B. et al. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Invest. 122, 2911–2915 (2012).
Moya, I. M. et al. Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice. Science 366, 1029–1034 (2019).
Wang, J. et al. Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene 37, 3229–3242 (2018).
Yamada, D. et al. IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism. Hepatology 61, 1627–1642 (2015).
Lu, X. et al. YAP accelerates notch-driven cholangiocarcinogenesis via mTORC1 in mice. Am. J. Pathol. 191, 1651–1667 (2021).
Song, X. et al. Focal adhesion kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation. J. Hepatol. 75, 888–899 (2021).
White, S. M., Murakami, S. & Yi, C. The complex entanglement of Hippo-Yap/Taz signaling in tumor immunity. Oncogene 38, 2899–2909 (2019).
Lee, B. S. et al. Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma. Biochem. Biophys. Res. Commun. 491, 493–499 (2017).
Kim, M. H. et al. YAP-Induced PD-L1 expression drives immune evasion in BRAFi-resistant melanoma. Cancer Immunol. Res. 6, 255–266 (2018).
Janse van Rensburg, H. J. et al. The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1. Cancer Res. 78, 1457–1470 (2018).
Miao, J. et al. YAP regulates PD-L1 expression in human NSCLC cells. Oncotarget 8, 114576–114587 (2017).
Macek Jilkova, Z., Aspord, C. & Decaens, T. Predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of hepatocellular carcinoma: current status and challenges. Cancers (Basel) 11, 1554 (2019).
Moroishi, T. et al. The Hippo pathway kinases LATS1/2 suppress cancer immunity. Cell 167, 1525–1539.e17 (2016).
Guo, X. et al. Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev. 31, 247–259 (2017).
Kim, W. et al. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut 67, 1692–1703 (2018).
Hyun, J. et al. Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease. J. Hepatol. 75, 623–633 (2021).
Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26, 1300–1305 (2012).
Konstantinou, E. K. et al. Verteporfin-induced formation of protein cross-linked oligomers and high molecular weight complexes is mediated by light and leads to cell toxicity. Sci. Rep. 7, 46581 (2017).
Chen, L. et al. Structural basis of YAP recognition by TEAD4 in the Hippo pathway. Genes Dev. 24, 290–300 (2010).
Bum-Erdene, K. et al. Small-molecule covalent modification of conserved cysteine leads to allosteric inhibition of the TEAD⋅Yap protein-protein interaction. Cell Chem. Biol. 26, 378–389.e13 (2019).
Holden, J. K. et al. Small molecule dysregulation of TEAD lipidation induces a dominant-negative inhibition of Hippo pathway signaling. Cell Rep. 31, 107809 (2020).
Kurppa, K. J. et al. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 37, 104–122.e12 (2020).
Jiao, S. et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25, 166–180 (2014).
Wang, W. et al. Tankyrase inhibitors target YAP by stabilizing angiomotin family proteins. Cell Rep. 13, 524–532 (2015).
Jia, J. et al. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS ONE 12, e0184068 (2017).
Zanconato, F. et al. Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4. Nat. Med. 24, 1599–1610 (2018).
Yin, H. et al. RNAi-nanoparticulate manipulation of gene expression as a new functional genomics tool in the liver. J. Hepatol. 64, 899–907 (2016).
Haak, A. J. et al. Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis. Sci. Transl. Med. 11, eaau6296 (2019).
Alsamman, S. et al. Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice. Sci. Transl. Med. 12, eaay8798 (2020).
Acknowledgements
The authors are grateful to all the members of the laboratory of F.D.C. for insightful discussions. The authors were supported by grants from the National Institutes of Health (AR064036 and DK099559 to F.D.C., 1F32CA254433-01 to J.O.R.) and the Cholangiocarcinoma Foundation (2019 Mark R. Clements Memorial Research Fellowship Award to J.O.R.). F.D.C. is an HHMI scholar.
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F.D.C. made a substantial contribution to discussion of content, and reviewed/edited the manuscript before submission. J.O.R. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed/edited the manuscript before submission.
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F.D.C. holds equity interests and is on the scientific advisory board of Fog Therapeutics. F.D.C. has applied for patents related to inhibition of YAP/TEAD function.
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Nature Reviews Gastroenterology & Hepatology thanks Xin Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Russell, J.O., Camargo, F.D. Hippo signalling in the liver: role in development, regeneration and disease. Nat Rev Gastroenterol Hepatol 19, 297–312 (2022). https://doi.org/10.1038/s41575-021-00571-w
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DOI: https://doi.org/10.1038/s41575-021-00571-w
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