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Clinical implications of the Hippo-YAP pathway in multiple cancer contexts

  • Kim, Han-Byul (LG Chem, Department of Life Sciences, R&D Park) ;
  • Myung, Seung-Jae (Biomedical Research Center, Asan Institute for Life Sciences)
  • Received : 2017.12.20
  • Published : 2018.03.31

Abstract

The Hippo pathway plays prominent and widespread roles in various forms of human carcinogenesis. Specifically, the Yes-associated protein (YAP), a downstream effector of the Hippo pathway, can lead to excessive cell proliferation and the inhibition of apoptosis, resulting in tumorigenesis. It was reported that the YAP is strongly elevated in multiple types of human malignancies such as breast, lung, small intestine, colon, and liver cancers. Recent work indicates that, surprisingly, Hippo signaling components' (SAV1, MST1/2, Lats1/2) mutations are virtually absent in human cancer, rendering this signaling an unlikely candidate to explain the vigorous activation of the YAP in most, if not all human tumors and an activated YAP promotes the resistance to RAF-, MAPK/ERK Kinase (MEK)-, and Epidermal growth factor receptor (EGFR)-targeted inhibitor therapy. The analysis of YAP expressions can facilitate the identification of patients who respond better to an anti-cancer drug treatment comprising RAF-, MEK-, and EGFR-targeted inhibitors. The prominence of YAP for those aspects of cancer biology denotes that these factors are ideal targets for the development of anti-cancer medications. Therefore, our report strongly indicates that the YAP is of potential prognostic utility and druggability in various human cancers.

Keywords

References

  1. Harvey K and Tapon N (2007) The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nat Rev Cancer 7, 182-191 https://doi.org/10.1038/nrc2070
  2. Meignin C, Alvarez-Garcia I, Davis I and Palacios IM (2007) The salvador-warts-hippo pathway is required for epithelial proliferation and axis specification in Drosophila. Curr Biol 17, 1871-1878 https://doi.org/10.1016/j.cub.2007.09.062
  3. Zhang X, Milton CC, Humbert PO and Harvey KF (2009) Transcriptional output of the Salvador/warts/hippo pathway is controlled in distinct fashions in Drosophila melanogaster and mammalian cell lines. Cancer Res 69, 6033-6041
  4. Huang J, Wu S, Barrera J, Matthews K and Pan D (2005) The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122, 421-434 https://doi.org/10.1016/j.cell.2005.06.007
  5. Kango-Singh M and Singh A (2009) Singh, Regulation of organ size: insights from the Drosophila Hippo signaling pathway. Dev Dyn 238, 1627-1637 https://doi.org/10.1002/dvdy.21996
  6. Pan D (2007) Hippo signaling in organ size control. Genes Dev 21, 886-897 https://doi.org/10.1101/gad.1536007
  7. Zhang L, Yue T and Jiang J (2009) Hippo signaling pathway and organ size control. Fly (Austin) 3, 68-73 https://doi.org/10.4161/fly.3.1.7788
  8. Wang K, Degerny C, Xu M and Yang XJ (2009) YAP, TAZ, and Yorkie: a conserved family of signal-responsive transcriptional coregulators in animal development and human disease. Biochem Cell Biol 87, 77-91 https://doi.org/10.1139/O08-114
  9. Xu T, Wang W, Zhang S, Stewart RA and Yu W (1995) Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053-1063
  10. Pantalacci S, Tapon N and Leopold P (2003) The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5, 921-927 https://doi.org/10.1038/ncb1051
  11. Jia J, Zhang W, Wang B, Trinko R and Jiang J (2003) The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes Dev 17, 2514-2519 https://doi.org/10.1101/gad.1134003
  12. Udan RS, Kango-Singh M, Nolo R, Tao C and Halder G (2003) Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol 5, 914-920 https://doi.org/10.1038/ncb1050
  13. Piccolo S, Dupont S and Cordenonsi M (2014) The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 94, 1287-1312 https://doi.org/10.1152/physrev.00005.2014
  14. Harvey KF, Zhang X and Thomas DM (2013) Thomas, The Hippo pathway and human cancer. Nat Rev Cancer 13, 246-257 https://doi.org/10.1038/nrc3458
  15. Yu FX, Zhao B and Guan KL (2015) Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163, 811-828 https://doi.org/10.1016/j.cell.2015.10.044
  16. Piccolo S, Cordenonsi M and Dupont S (2013) Molecular pathways: YAP and TAZ take center stage in organ growth and tumorigenesis. Clin Cancer Res 19, 4925-4930 https://doi.org/10.1158/1078-0432.CCR-12-3172
  17. Keren-Paz A, Emmanuel R and Samuels Y (2015) YAP and the drug resistance highway. Nat Genet 47, 193-194 https://doi.org/10.1038/ng.3228
  18. Jiao S, Wang H and Shi Z (2014) A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25, 166-180 https://doi.org/10.1016/j.ccr.2014.01.010
  19. Steinhardt AA, Gayyed MF, Klein AP et al (2008) Expression of Yes-associated protein in common solid tumors. Hum Pathol 39, 1582-1589 https://doi.org/10.1016/j.humpath.2008.04.012
  20. Wang Y, Xie C, Li Q, Xu K and Wang E (2013) Clinical and prognostic significance of Yes-associated protein in colorectal cancer. Tumour Biol 34, 2169-2174 https://doi.org/10.1007/s13277-013-0751-x
  21. Camargo FD, Gokhale S, Johnnidis JB et al (2007) YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17, 2054-2060 https://doi.org/10.1016/j.cub.2007.10.039
  22. Chan EH, Nousiainen M, Chalamalasetty RB, Schafer A, Nigg EA and Sillje HH (2005) The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 24, 2076-2086 https://doi.org/10.1038/sj.onc.1208445
  23. Hao Y, Chun A, Cheung K, Rashidi B and Yang X (2008) Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem 283, 5496-5509 https://doi.org/10.1074/jbc.M709037200
  24. Zhao B, Ye X, Yu J et al (2008) TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22, 1962-1971 https://doi.org/10.1101/gad.1664408
  25. Flaherty KT, Hodi FS and Fisher DE (2012) From genes to drugs: targeted strategies for melanoma. Nat Rev Cancer 12, 349-361 https://doi.org/10.1038/nrc3218
  26. Eggermont AM and Robert C (2012) Melanoma in 2011: a new paradigm tumor for drug development. Nat Rev Clin Oncol 9, 74-76 https://doi.org/10.1038/nrclinonc.2011.201
  27. Jones PS and Jones D (2012) New regulatory framework for cancer drug development. Drug Discov Today 17, 227-231 https://doi.org/10.1016/j.drudis.2011.12.015
  28. Mullard A (2015) The Roadmap Epigenomics Project opens new drug development avenues. Nat Rev Drug Discov 14, 223-225 https://doi.org/10.1038/nrd4582
  29. Vukicevic S (2016) Current Challenges and Hurdles in New Drug Development. Clin Ther 38, e3
  30. De Angelis ML, De Maria R and Baiocchi M (2018) How to Assess Drug Resistance in Cancer Stem Cells. Methods Mol Biol 1692, 107-115
  31. Emery CM, Vijayendran KG, Zipser MC et al (2009) MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A 106, 20411-20416 https://doi.org/10.1073/pnas.0905833106
  32. Guang MHZ, McCann A, Bianchi G et al (2018) Overcoming multiple myeloma drug resistance in the era of cancer 'omics'. Leuk Lymphoma 59, 542-561 https://doi.org/10.1080/10428194.2017.1337115
  33. Norouzi-Barough L, Sarookhani MR, Sharifi M, Moghbelinejad S, Jangjoo S and Salehi R (2017) Molecular Mechanisms of Drug Resistance in Ovarian Cancer. J Cell Physiol [Epub ahead of print]
  34. Siegfried Z and Karni R (2017) The role of alternative splicing in cancer drug resistance. Curr Opin Genet Dev 48, 16-21
  35. Mansoori B, Mohammadi A, Davudian S, Shirjang S and Baradaran B (2017) The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull 7, 339-348 https://doi.org/10.15171/apb.2017.041
  36. Lin CH, Pelissier FA, Zhang H et al (2015) Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors. Mol Biol Cell 26, 3946-3953 https://doi.org/10.1091/mbc.E15-07-0456
  37. Lin L, Sabnis AJ, Chan E et al (2015) The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 47, 250-256 https://doi.org/10.1038/ng.3218
  38. Guo L and Teng L (2015) YAP/TAZ for cancer therapy: opportunities and challenges (review). Int J Oncol 46, 1444-1452 https://doi.org/10.3892/ijo.2015.2877
  39. Moroishi T, Hansen CG and Guan KL (2015) The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 15, 73-79 https://doi.org/10.1038/nrc3876
  40. Ma Y, Yang Y, Wang F, Wei Q and Qin H (2015) Hippo-YAP signaling pathway: A new paradigm for cancer therapy. Int J Cancer 137, 2275-2286 https://doi.org/10.1002/ijc.29073
  41. Kim MH, Kim J, Hong H et al (2016) Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J 35, 462-478 https://doi.org/10.15252/embj.201592081
  42. Hsu PC, You B, Yang YL et al (2016) YAP promotes erlotinib resistance in human non-small cell lung cancer cells. Oncotarget 7, 51922-51933
  43. Zanconato F, Battilana G, Cordenonsi M and Piccolo S (2016) YAP/TAZ as therapeutic targets in cancer. Curr Opin Pharmacol 29, 26-33 https://doi.org/10.1016/j.coph.2016.05.002
  44. Andl T, Zhou L, Yang K, Kadekaro AL and Zhang Y (2017) YAP and WWTR1: New targets for skin cancer treatment. Cancer Lett 396, 30-41 https://doi.org/10.1016/j.canlet.2017.03.001
  45. Kim MH and Kim J (2017) Role of YAP/TAZ transcriptional regulators in resistance to anti-cancer therapies. Cell Mol Life Sci 74, 1457-1474 https://doi.org/10.1007/s00018-016-2412-x
  46. Sun PL, Jin Y and Chung JH (2017) Reply: YAP is a Key Factor to Improve the Management of Cancer Treatments. Ann Surg Oncol 24, 644-645 https://doi.org/10.1245/s10434-017-6205-8
  47. Zhang Y, Shen H, Withers HG et al (2017) VGLL4 Selectively Represses YAP-Dependent Gene Induction and Tumorigenic Phenotypes in Breast Cancer. Sci Rep 7, 6190 https://doi.org/10.1038/s41598-017-06227-7
  48. Ahmed AA, Mohamed AD, Gener M, Li W and Taboada E (2017) YAP and the Hippo pathway in pediatric cancer. Mol Cell Oncol 4, e1295127 https://doi.org/10.1080/23723556.2017.1295127
  49. Avril T and Chevet E (2015) Proteostasis trumps YAP in colon cancer. Sci Signal 8, fs18 https://doi.org/10.1126/scisignal.aad3123
  50. Cao L, Sun PL, Yao M, Jia M and Gao H (2017) Expression of YES-associated protein (YAP) and its clinical significance in breast cancer tissues. Hum Pathol 68, 166-174 https://doi.org/10.1016/j.humpath.2017.08.032
  51. Eibl G and Rozengurt E (2017) YAP, and obesity in pancreatic cancer: A signaling network with multiple loops. Semin Cancer Biol [Epub ahead of print]
  52. Feng J, Gou J, Jia J, Yi T, Cui T and Li Z (2016) Verteporfin, a suppressor of YAP-TEAD complex, presents promising antitumor properties on ovarian cancer. Onco Targets Ther 9, 5371-5381 https://doi.org/10.2147/OTT.S109979
  53. Kim HM, Jung WH and Koo JS (2015) Expression of Yes-associated protein (YAP) in metastatic breast cancer. Int J Clin Exp Pathol 8, 11248-11257
  54. Maugeri-Sacca M, Barba M, Pizzuti L et al (2015) The Hippo transducers TAZ and YAP in breast cancer: oncogenic activities and clinical implications. Expert Rev Mol Med 17, e14 https://doi.org/10.1017/erm.2015.12
  55. Zanconato F, Cordenonsi M and Piccolo S (2016) YAP/TAZ at the Roots of Cancer. Cancer Cell 29, 783-803 https://doi.org/10.1016/j.ccell.2016.05.005
  56. Zhou GX, Li XY, Zhang Q et al (2013) Effects of the hippo signaling pathway in human gastric cancer. Asian Pac J Cancer Prev 14, 5199-5205 https://doi.org/10.7314/APJCP.2013.14.9.5199
  57. Formisano L, Jansen VM, Marciano R and Bianco R (2017) From biology to therapy: Improvements of therapeutic options in Lung cancer. Anticancer Agents Med Chem [Epub ahead of print]
  58. Lemjabbar-Alaoui H, Hassan OU, Yang YW and Buchanan P (2015) Lung cancer: Biology and treatment options. Biochim Biophys Acta 1856, 189-210
  59. Suda K and Mitsudomi T (2017) [Molecular Biology for Surgical Treatment of Lung Cancer]. Kyobu Geka 70, 4-8
  60. Lee BS, Park DI, Lee DH et al (2017) Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma. Biochem Biophys Res Commun 491, 493-499 https://doi.org/10.1016/j.bbrc.2017.07.007
  61. Lee JE, Park HS, Lee D et al (2016) Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance. Biochem Biophys Res Commun 474, 154-160 https://doi.org/10.1016/j.bbrc.2016.04.089
  62. Karachaliou N, Chaib I, Pilotto S et al (2016) 76P An innovative co-targeting of signal transducer and activator of transcription 3 (STAT3) and Src-YAP pathways in EGFR mutant non-small cell lung cancer (NSCLC). J Thorac Oncol 11, S87-S88
  63. Wang H, Lu B, Castillo J et al (2016) Tankyrase Inhibitor Sensitizes Lung Cancer Cells to Endothelial Growth Factor Receptor (EGFR) Inhibition via Stabilizing Angiomotins and Inhibiting YAP Signaling. J Biol Chem 291, 15256-15266 https://doi.org/10.1074/jbc.M116.722967
  64. Parsa Y, Mirmalek SA, Kani FE et al (2016) A Review of the Clinical Implications of Breast Cancer Biology. Electron Physician 8, 2416-2424 https://doi.org/10.19082/2416
  65. Chan SW, Lim CJ, Guo K et al (2008) A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res 68, 2592-2598 https://doi.org/10.1158/0008-5472.CAN-07-2696
  66. Cordenonsi M, Zanconato F, Azzolin L et al (2011) The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147, 759-772 https://doi.org/10.1016/j.cell.2011.09.048
  67. Diaz-Martin J, Lopez-Garcia MA, Romero-Perez L et al (2015) Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer. Endocr Relat Cancer 22, 443-454 https://doi.org/10.1530/ERC-14-0456
  68. Li YW, Shen H, Frangou C et al (2015) Characterization of TAZ domains important for the induction of breast cancer stem cell properties and tumorigenesis. Cell Cycle 14, 146-156 https://doi.org/10.4161/15384101.2014.967106
  69. Bartucci M, Dattilo R, Moriconi C et al (2015) TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene 34, 681-690 https://doi.org/10.1038/onc.2014.5
  70. Yuan M, Tomlinson V, Lara R et al (2008) Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ 15, 1752-1759 https://doi.org/10.1038/cdd.2008.108
  71. Kim SK, Jung WH and Koo JS (2014) Yes-associated protein (YAP) is differentially expressed in tumor and stroma according to the molecular subtype of breast cancer. Int J Clin Exp Pathol 7, 3224-3234
  72. Jaramillo-Rodriguez Y, Cerda-Flores RM, Ruiz-Ramos R, Lopez-Marquez FC and Calderon-Garciduenas AL (2014) YAP expression in normal and neoplastic breast tissue: an immunohistochemical study. Arch Med Res 45, 223-228 https://doi.org/10.1016/j.arcmed.2014.01.010
  73. Kagawa Y, Ishii H, Sekimoto M, Doki Y and Mori M (2011) [Molecular biology of colon cancer]. Nihon Rinsho 69, 67-71
  74. Zhang L and Yu J (2013) Role of apoptosis in colon cancer biology, therapy, and prevention. Curr Colorectal Cancer Rep 9
  75. Kim HB, Kim M, Park YS et al (2017) Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice. Gastroenterology 152, 616-630 https://doi.org/10.1053/j.gastro.2016.11.005
  76. Ling HH, Kuo CC, Lin BX, Huang YH and Lin CW (2017) Elevation of YAP promotes the epithelial-mesenchymal transition and tumor aggressiveness in colorectal cancer. Exp Cell Res 350, 218-225 https://doi.org/10.1016/j.yexcr.2016.11.024
  77. Lee KW, Lee SS, Kim SB et al (2015) Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients. Clin Cancer Res 21, 357-364 https://doi.org/10.1158/1078-0432.CCR-14-1374
  78. Jerhammar F, Johansson AC, Ceder R et al (2014) YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. Oral Oncol 50, 832-839 https://doi.org/10.1016/j.oraloncology.2014.06.003
  79. Hernanda PY, Pedroza-Gonzalez A, Sprengers D, Peppelenbosch MP and Pan Q (2014) Multipotent mesenchymal stromal cells in liver cancer: implications for tumor biology and therapy. Biochim Biophys Acta 1846, 439-445
  80. Kudo M (2012) Targeted therapy for liver cancer: updated review in 2012. Curr Cancer Drug Targets 12, 1062-1072
  81. Oishi N, Yamashita T and Kaneko S (2014) Molecular biology of liver cancer stem cells. Liver Cancer 3, 71-84 https://doi.org/10.1159/000343863
  82. Kim Y and Jho EH (2017) Deubiquitinase YOD1: the potent activator of YAP in hepatomegaly and liver cancer. BMB Rep 50, 281-282 https://doi.org/10.5483/BMBRep.2017.50.6.078
  83. Liu AM, Xu MZ, Chen J, Poon RT and Luk JM (2010) Targeting YAP and Hippo signaling pathway in liver cancer. Expert Opin Ther Targets 14, 855-868 https://doi.org/10.1517/14728222.2010.499361
  84. Liu AM, Xu Z and Luk JM (2012) An update on targeting Hippo-YAP signaling in liver cancer. Expert Opin Ther Targets 16, 243-247 https://doi.org/10.1517/14728222.2012.662958
  85. Liu-Chittenden Y, Huang B, Shim JS et al (2012) Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 26, 1300-1305 https://doi.org/10.1101/gad.192856.112
  86. Yimlamai D, Fowl BH and Camargo FD (2015) Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J Hepatol 63, 1491-1501 https://doi.org/10.1016/j.jhep.2015.07.008
  87. Han SX, Bai E, Jin GH et al (2014) Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma. J Immunol Res 2014, 261365
  88. Cervantes A, Rodriguez Braun E, Perez Fidalgo A and Chirivella Gonzalez I (2007) Molecular biology of gastric cancer. Clin Transl Oncol 9, 208-215 https://doi.org/10.1007/s12094-007-0041-4
  89. Dreznik A, Purim O, Idelevich E et al (2012) Gastric cancer: biology and clinical manifestations in Israel. J Surg Oncol 105, 316-322 https://doi.org/10.1002/jso.22078
  90. El-Rifai W and Powell SM (2002) Molecular biology of gastric cancer. Semin Radiat Oncol 12, 128-140 https://doi.org/10.1053/srao.2002.30815
  91. Cai J, Zhang N, Zheng Y, de Wilde RF, Maitra A and Pan D (2010) The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev 24, 2383-2388 https://doi.org/10.1101/gad.1978810
  92. Zhou D, Zhang Y, Wu H et al (2011) Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc Natl Acad Sci U S A 108, E1312- E1320 https://doi.org/10.1073/pnas.1110428108
  93. Kaan HYK, Chan SW, Tan SKJ et al (2017) Crystal structure of TAZ-TEAD complex reveals a distinct interaction mode from that of YAP-TEAD complex. Sci Rep 7, 2035 https://doi.org/10.1038/s41598-017-02219-9
  94. Zhang Z, Lin Z, Zhou Z et al (2014) Structure-Based Design and Synthesis of Potent Cyclic Peptides Inhibiting the YAP-TEAD Protein-Protein Interaction. ACS Med Chem Lett 5, 993-998 https://doi.org/10.1021/ml500160m

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