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Role of YAP/TAZ transcriptional regulators in resistance to anti-cancer therapies

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Abstract

A diverse range of drug resistance mechanisms in cancer cells and their microenvironment significantly reduces the effectiveness of anti-cancer therapies. Growing evidence suggests that transcriptional effectors of the Hippo pathway, YAP and TAZ, promote resistance to various anti-cancer therapies, including cytotoxic chemotherapy, molecular targeted therapy, and radiation therapy. Here, we overview the role of YAP and TAZ as drug resistance mediators, and also discuss potential upstream regulators and downstream targets of YAP/TAZ in cancer. The widespread involvement of YAP and TAZ in resistance mechanisms suggests that therapeutic targeting of YAP and TAZ may expedite the development of effective anti-resistance therapies.

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References

  1. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726

    Article  CAS  PubMed  Google Scholar 

  2. Lavi O (2015) Redundancy: a critical obstacle to improving cancer therapy. Cancer Res 75:808–812

    Article  CAS  PubMed  Google Scholar 

  3. Saunders NA, Simpson F, Thompson EW, Hill MM, Endo-Munoz L, Leggatt G, Minchin RF, Guminski A (2012) Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives. EMBO Mol Med 4:675–684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lackner MR, Wilson TR, Settleman J (2012) Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol 8:999–1014

    Article  CAS  PubMed  Google Scholar 

  5. Taylor ST, Hickman JA, Dive C (2000) Epigenetic determinants of resistance to etoposide regulation of Bcl-X(L) and Bax by tumor microenvironmental factors. J Natl Cancer Inst 92:18–23

    Article  CAS  PubMed  Google Scholar 

  6. Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM, Zecchin D, Hobor S, Bajpe PK, Lieftink C, Mateus C, Vagner S, Grernrum W, Hofland I, Schlicker A, Wessels LF, Beijersbergen RL, Bardelli A, Di Nicolantonio F, Eggermont AM, Bernards R (2014) Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508:118–122

    Article  CAS  PubMed  Google Scholar 

  7. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487:500–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454

    Article  CAS  PubMed  Google Scholar 

  9. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M (2015) AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372:1689–1699

    Article  PubMed  Google Scholar 

  10. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877–1888

    Article  PubMed  CAS  Google Scholar 

  11. Zhao B, Tumaneng K, Guan KL (2011) The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol 13:877–883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yu FX, Zhao B, Guan KL (2015) Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163:811–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zanconato F, Cordenonsi M, Piccolo S (2016) YAP/TAZ at the Roots of Cancer. Cancer Cell 29:783–803

    Article  CAS  PubMed  Google Scholar 

  14. Moroishi T, Hansen CG, Guan KL (2015) The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 15:73–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Harvey KF, Zhang X, Thomas DM (2013) The hippo pathway and human cancer. Nat Rev Cancer 13:246–257

    Article  CAS  PubMed  Google Scholar 

  16. Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ (1995) The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev 9:534–546

    Article  CAS  PubMed  Google Scholar 

  17. Wu S, Huang J, Dong J, Pan D (2003) 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

    Article  CAS  PubMed  Google Scholar 

  18. Xu T, Wang W, Zhang S, Stewart RA, Yu W (1995) Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121:1053–1063

    CAS  PubMed  Google Scholar 

  19. Lai ZC, Wei X, Shimizu T, Ramos E, Rohrbaugh M, Nikolaidis N, Ho LL, Li Y (2005) Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120:675–685

    Article  CAS  PubMed  Google Scholar 

  20. Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber D, Hariharan IK (2002) salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110:467–478

    Article  CAS  PubMed  Google Scholar 

  21. Harvey KF, Pfleger CM, Hariharan IK (2003) The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114:457–467

    Article  CAS  PubMed  Google Scholar 

  22. Pantalacci S, Tapon N, Leopold P (2003) The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5:921–927

    Article  CAS  PubMed  Google Scholar 

  23. Jia J, Zhang W, Wang B, Trinko R, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huang J, Wu S, Barrera J, Matthews K, 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

    Article  CAS  PubMed  Google Scholar 

  25. Meng Z, Moroishi T, Guan KL (2016) Mechanisms of Hippo pathway regulation. Genes Dev 30:1–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL (2007) Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21:2747–2761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao B, Li L, Tumaneng K, Wang CY, Guan KL (2010) A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev 24:72–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL (2008) TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22:1962–1971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B, Rosato A, Bicciato S, Cordenonsi M, Piccolo S (2015) Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol 17:1218–1227

    Article  CAS  PubMed  Google Scholar 

  30. Zaidi SK, Sullivan AJ, Medina R, Ito Y, van Wijnen AJ, Stein JL, Lian JB, Stein GS (2004) Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J 23:790–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, Rossant J, Wrana JL (2010) The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell 19:831–844

    Article  CAS  PubMed  Google Scholar 

  32. Kim M, Kim T, Johnson RL, Lim DS (2015) Transcriptional co-repressor function of the hippo pathway transducers YAP and TAZ. Cell Rep 11:270–282

    Article  CAS  PubMed  Google Scholar 

  33. Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S, Xiong Y, Lei QY, Guan KL (2009) TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J Biol Chem 284:13355–13362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stein C, Bardet AF, Roma G, Bergling S, Clay I, Ruchti A, Agarinis C, Schmelzle T, Bouwmeester T, Schubeler D, Bauer A (2015) YAP1 exerts its transcriptional control via TEAD-mediated activation of enhancers. PLoS Genet 11:e1005465

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S (2011) The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147:759–772

    Article  CAS  PubMed  Google Scholar 

  36. Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo S (2013) A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154:1047–1059

    Article  CAS  PubMed  Google Scholar 

  37. Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL (2012) Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26:54–68

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474:179–183

    Article  CAS  PubMed  Google Scholar 

  39. Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, Harrington K, Williamson P, Moeendarbary E, Charras G, Sahai E (2013) Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol 15:637–646

    Article  CAS  PubMed  Google Scholar 

  40. Wada K, Itoga K, Okano T, Yonemura S, Sasaki H (2011) Hippo pathway regulation by cell morphology and stress fibers. Development 138:3907–3914

    Article  CAS  PubMed  Google Scholar 

  41. Mo JS, Meng Z, Kim YC, Park HW, Hansen CG, Kim S, Lim DS, Guan KL (2015) Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol 17:500–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. DeRan M, Yang J, Shen CH, Peters EC, Fitamant J, Chan P, Hsieh M, Zhu S, Asara JM, Zheng B, Bardeesy N, Liu J, Wu X (2014) Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep 9:495–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, Manfrin A, Ingallina E, Sommaggio R, Piazza S, Rosato A, Piccolo S, Del Sal G (2014) Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol 16:357–366

    Article  CAS  PubMed  Google Scholar 

  44. Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, Zhao J, Yuan H, Tumaneng K, Li H, Fu XD, Mills GB, Guan KL (2012) Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150:780–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Reddy BV, Irvine KD (2013) Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev Cell 24:459–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA (2009) YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 11:1444–1450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hiemer SE, Szymaniak AD, Varelas X (2014) The transcriptional regulators TAZ and YAP direct transforming growth factor beta-induced tumorigenic phenotypes in breast cancer cells. J Biol Chem 289:13461–13474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Azzolin L, Zanconato F, Bresolin S, Forcato M, Basso G, Bicciato S, Cordenonsi M, Piccolo S (2012) Role of TAZ as mediator of Wnt signaling. Cell 151:1443–1456

    Article  CAS  PubMed  Google Scholar 

  49. Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, Bresolin S, Frasson C, Basso G, Guzzardo V, Fassina A, Cordenonsi M, Piccolo S (2014) YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158:157–170

    Article  CAS  PubMed  Google Scholar 

  50. Park HW, Kim YC, Yu B, Moroishi T, Mo JS, Plouffe SW, Meng Z, Lin KC, Yu FX, Alexander CM, Wang CY, Guan KL (2015) Alternative Wnt signaling activates YAP/TAZ. Cell 162:780–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR (2007) YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17:2054–2060

    Article  CAS  PubMed  Google Scholar 

  52. Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, Lauwers GY, Thasler W, Lee JT, Avruch J, Bardeesy N (2009) Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16:425–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D (2007) Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130:1120–1133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, Martin JF (2011) Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332:458–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lee JH, Kim TS, Yang TH, Koo BK, Oh SP, Lee KP, Oh HJ, Lee SH, Kong YY, Kim JM, Lim DS (2008) A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J 27:1231–1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lian I, Kim J, Okazawa H, Zhao J, Zhao B, Yu J, Chinnaiyan A, Israel MA, Goldstein LS, Abujarour R, Ding S, Guan KL (2010) The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev 24:1106–1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cai J, Maitra A, Anders RA, Taketo MM, Pan D (2015) beta-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev 29:1493–1506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Grijalva JL, Huizenga M, Mueller K, Rodriguez S, Brazzo J, Camargo F, Sadri-Vakili G, Vakili K (2014) Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am J Physiol Gastrointest Liver Physiol 307:G196–G204

    Article  CAS  PubMed  Google Scholar 

  59. Karpowicz P, Perez J, Perrimon N (2010) The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137:4135–4145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Xin M, Kim Y, Sutherland LB, Murakami M, Qi X, McAnally J, Porrello ER, Mahmoud AI, Tan W, Shelton JM, Richardson JA, Sadek HA, Bassel-Duby R, Olson EN (2013) Hippo pathway effector Yap promotes cardiac regeneration. Proc Natl Acad Sci USA 110:13839–13844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Heallen T, Morikawa Y, Leach J, Tao G, Willerson JT, Johnson RL, Martin JF (2013) Hippo signaling impedes adult heart regeneration. Development 140:4683–4690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA (2006) Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA 103:12405–12410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhou D, Zhang Y, Wu H, Barry E, Yin Y, Lawrence E, Dawson D, Willis JE, Markowitz SD, Camargo FD, Avruch J (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 USA 108:E1312–E1320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nishio M, Hamada K, Kawahara K, Sasaki M, Noguchi F, Chiba S, Mizuno K, Suzuki SO, Dong Y, Tokuda M, Morikawa T, Hikasa H, Eggenschwiler J, Yabuta N, Nojima H, Nakagawa K, Hata Y, Nishina H, Mimori K, Mori M, Sasaki T, Mak TW, Nakano T, Itami S, Suzuki A (2012) Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice. J Clin Invest 122:4505–4518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mohseni M, Sun J, Lau A, Curtis S, Goldsmith J, Fox VL, Wei C, Frazier M, Samson O, Wong KK, Kim C, Camargo FD (2014) A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol 16:108–117

    Article  CAS  PubMed  Google Scholar 

  66. Lee SE, Lee JU, Lee MH, Ryu MJ, Kim SJ, Kim YK, Choi MJ, Kim KS, Kim JM, Kim JW, Koh YW, Lim DS, Jo YS, Shong M (2013) RAF kinase inhibitor-independent constitutive activation of Yes-associated protein 1 promotes tumor progression in thyroid cancer. Oncogenesis 2:e55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Nguyen LT, Tretiakova MS, Silvis MR, Lucas J, Klezovitch O, Coleman I, Bolouri H, Kutyavin VI, Morrissey C, True LD, Nelson PS, Vasioukhin V (2015) ERG activates the YAP1 transcriptional program and induces the development of age-related prostate tumors. Cancer Cell 27:797–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. He C, Mao D, Hua G, Lv X, Chen X, Angeletti PC, Dong J, Remmenga SW, Rodabaugh KJ, Zhou J, Lambert PF, Yang P, Davis JS, Wang C (2015) The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Mol Med 7:1426–1449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Eisinger-Mathason TS, Mucaj V, Biju KM, Nakazawa MS, Gohil M, Cash TP, Yoon SS, Skuli N, Park KM, Gerecht S, Simon MC (2015) Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis. Proc Natl Acad Sci USA 112:E3402–E3411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn JM, Hall BD, Propping P, Rouleau GA (1996) Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. Am J Hum Genet 59:331–342

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Baser ME, Rai H, Wallace AJ, Evans DG (2005) Neurofibromatosis 2 (NF2) and malignant mesothelioma in a man with a constitutional NF2 missense mutation. Fam Cancer 4:321–322

    Article  CAS  PubMed  Google Scholar 

  72. Sekido Y (2011) Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation. Pathol Int 61:331–344

    Article  CAS  PubMed  Google Scholar 

  73. Chen HY, Yu SL, Ho BC, Su KY, Hsu YC, Chang CS, Li YC, Yang SY, Hsu PY, Ho H, Chang YH, Chen CY, Yang HI, Hsu CP, Yang TY, Chen KC, Hsu KH, Tseng JS, Hsia JY, Chuang CY, Yuan S, Lee MH, Liu CH, Wu GI, Hsiung CA, Chen YM, Wang CL, Huang MS, Yu CJ, Chen KY, Tsai YH, Su WC, Chen HW, Chen JJ, Chen CJ, Chang GC, Yang PC, Li KC (2015) R331W missense mutation of oncogene YAP1 Is a Germline risk allele for lung adenocarcinoma with medical actionability. J Clin Oncol 33:2303–2310

    Article  CAS  PubMed  Google Scholar 

  74. Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S, Lowe SW (2006) Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125:1253–1267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Muramatsu T, Imoto I, Matsui T, Kozaki K, Haruki S, Sudol M, Shimada Y, Tsuda H, Kawano T, Inazawa J (2011) YAP is a candidate oncogene for esophageal squamous cell carcinoma. Carcinogenesis 32:389–398

    Article  CAS  PubMed  Google Scholar 

  76. Fernandez LA, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, Taylor MD, Kenney AM (2009) YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 23:2729–2741

    Article  CAS  Google Scholar 

  77. Errani C, Zhang L, Sung YS, Hajdu M, Singer S, Maki RG, Healey JH, Antonescu CR (2011) A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer 50:644–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Antonescu CR, Le Loarer F, Mosquera JM, Sboner A, Zhang L, Chen CL, Chen HW, Pathan N, Krausz T, Dickson BC, Weinreb I, Rubin MA, Hameed M, Fletcher CD (2013) Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer 52:775–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Sekido Y (2011) LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res 71:873–883

    Article  CAS  PubMed  Google Scholar 

  80. Bonilla X, Parmentier L, King B, Bezrukov F, Kaya G, Zoete V, Seplyarskiy VB, Sharpe HJ, McKee T, Letourneau A, Ribaux PG, Popadin K, Basset-Seguin N, Chaabene RB, Santoni FA, Andrianova MA, Guipponi M, Garieri M, Verdan C, Grosdemange K, Sumara O, Eilers M, Aifantis I, Michielin O, de Sauvage FJ, Antonarakis SE, Nikolaev SI (2016) Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat Genet 48:398–406

    Article  CAS  PubMed  Google Scholar 

  81. Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M, Zaidi MR, Ksander BR, Merlino G, Sodhi A, Chen Q, Gutkind JS (2014) Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 25:831–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yu FX, Luo J, Mo JS, Liu G, Kim YC, Meng Z, Zhao L, Peyman G, Ouyang H, Jiang W, Zhao J, Chen X, Zhang L, Wang CY, Bastian BC, Zhang K, Guan KL (2014) Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25:822–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, Montgomery EA, Anders RA (2008) Expression of Yes-associated protein in common solid tumors. Hum Pathol 39:1582–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, Lowe SW, Poon RT, Luk JM (2009) Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 115:4576–4585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X (2010) Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 101:1279–1285

    Article  CAS  PubMed  Google Scholar 

  86. Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox SB, group AS, Bowtell DD, Harvey KF (2011) The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene 30:2810–2822

    Article  CAS  PubMed  Google Scholar 

  87. Chan SW, Lim CJ, Guo K, Ng CP, Lee I, Hunziker W, Zeng Q, Hong W (2008) A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res 68:2592–2598

    Article  CAS  PubMed  Google Scholar 

  88. Zhang W, Nandakumar N, Shi Y, Manzano M, Smith A, Graham G, Gupta S, Vietsch EE, Laughlin SZ, Wadhwa M, Chetram M, Joshi M, Wang F, Kallakury B, Toretsky J, Wellstein A, Yi C (2014) Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci Signal 7:ra42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Gregorieff A, Liu Y, Inanlou MR, Khomchuk Y, Wrana JL (2015) Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. Nature 526:715–718

    Article  CAS  PubMed  Google Scholar 

  90. Galli GG, Carrara M, Yuan WC, Valdes-Quezada C, Gurung B, Pepe-Mooney B, Zhang T, Geeven G, Gray NS, de Laat W, Calogero RA, Camargo FD (2015) YAP drives growth by controlling transcriptional pause release from dynamic enhancers. Mol Cell 60:328–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kim T, Yang SJ, Hwang D, Song J, Kim M, Kyum Kim S, Kang K, Ahn J, Lee D, Kim MY, Kim S, Seung Koo J, Seok Koh S, Kim SY, Lim DS (2015) A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness. Nat Commun 6:10186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bartucci M, Dattilo R, Moriconi C, Pagliuca A, Mottolese M, Federici G, Benedetto AD, Todaro M, Stassi G, Sperati F, Amabile MI, Pilozzi E, Patrizii M, Biffoni M, Maugeri-Sacca M, Piccolo S, De Maria R (2015) TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene 34:681–690

    Article  CAS  PubMed  Google Scholar 

  93. Lehmann W, Mossmann D, Kleemann J, Mock K, Meisinger C, Brummer T, Herr R, Brabletz S, Stemmler MP, Brabletz T (2016) ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types. Nat Commun 7:10498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Nallet-Staub F, Marsaud V, Li L, Gilbert C, Dodier S, Bataille V, Sudol M, Herlyn M, Mauviel A (2014) Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous melanoma. J Invest Dermatol 134:123–132

    Article  CAS  PubMed  Google Scholar 

  95. Lamar JM, Stern P, Liu H, Schindler JW, Jiang ZG, Hynes RO (2012) The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain. Proc Natl Acad Sci USA 109:E2441–E2450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Basu S, Totty NF, Irwin MS, Sudol M, Downward J (2003) Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell 11:11–23

    Article  CAS  PubMed  Google Scholar 

  97. Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G (2001) Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem 276:15164–15173

    Article  CAS  PubMed  Google Scholar 

  98. Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Piazzolla D, Baccarini M, Vass JK, Kolch W, O’Neill E (2007) RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol Cell 27:962–975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, Gangeswaran R, Manson-Bishop C, Smith P, Danovi SA, Pardo O, Crook T, Mein CA, Lemoine NR, Jones LJ, Basu S (2008) Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ 15:1752–1759

    Article  CAS  PubMed  Google Scholar 

  100. Cottini F, Hideshima T, Xu C, Sattler M, Dori M, Agnelli L, ten Hacken E, Bertilaccio MT, Antonini E, Neri A, Ponzoni M, Marcatti M, Richardson PG, Carrasco R, Kimmelman AC, Wong KK, Caligaris-Cappio F, Blandino G, Kuehl WM, Anderson KC, Tonon G (2014) Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat Med 20:599–606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lai D, Ho KC, Hao Y, Yang X (2011) Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res 71:2728–2738

    Article  CAS  PubMed  Google Scholar 

  102. Zhao Y, Khanal P, Savage P, She YM, Cyr TD, Yang X (2014) YAP-induced resistance of cancer cells to antitubulin drugs is modulated by a Hippo-independent pathway. Cancer Res 74:4493–4503

    Article  CAS  PubMed  Google Scholar 

  103. Touil Y, Igoudjil W, Corvaisier M, Dessein AF, Vandomme J, Monte D, Stechly L, Skrypek N, Langlois C, Grard G, Millet G, Leteurtre E, Dumont P, Truant S, Pruvot FR, Hebbar M, Fan F, Ellis LM, Formstecher P, Van Seuningen I, Gespach C, Polakowska R, Huet G (2014) Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis. Clin Cancer Res 20:837–846

    Article  CAS  PubMed  Google Scholar 

  104. Song S, Honjo S, Jin J, Chang SS, Scott AW, Chen Q, Kalhor N, Correa AM, Hofstetter WL, Albarracin CT, Wu TT, Johnson RL, Hung MC, Ajani JA (2015) The Hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in esophageal cancer. Clin Cancer Res

  105. Cheung-Ong K, Giaever G, Nislow C (2013) DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol 20:648–659

    Article  CAS  PubMed  Google Scholar 

  106. Yoshikawa K, Noguchi K, Nakano Y, Yamamura M, Takaoka K, Hashimoto-Tamaoki T, Kishimoto H (2015) The Hippo pathway transcriptional co-activator, YAP, confers resistance to cisplatin in human oral squamous cell carcinoma. Int J Oncol 46:2364–2370

    CAS  PubMed  Google Scholar 

  107. Ciamporcero E, Shen H, Ramakrishnan S, Yu KuS, Chintala S, Shen L, Adelaiye R, Miles KM, Ullio C, Pizzimenti S, Daga M, Azabdaftari G, Attwood K, Johnson C, Zhang J, Barrera G, Pili R (2016) YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage. Oncogene 35:1541–1553

    Article  CAS  PubMed  Google Scholar 

  108. Xiao L, Shi XY, Zhang Y, Zhu Y, Zhu L, Tian W, Zhu BK, Wei ZL (2016) YAP induces cisplatin resistance through activation of autophagy in human ovarian carcinoma cells. Onco Targets Ther 9:1105–1114

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kapoor A, Yao W, Ying H, Hua S, Liewen A, Wang Q, Zhong Y, Wu CJ, Sadanandam A, Hu B, Chang Q, Chu GC, Al-Khalil R, Jiang S, Xia H, Fletcher-Sananikone E, Lim C, Horwitz GI, Viale A, Pettazzoni P, Sanchez N, Wang H, Protopopov A, Zhang J, Heffernan T, Johnson RL, Chin L, Wang YA, Draetta G, DePinho RA (2014) Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158:185–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F, Wang X, Schinzel AC, Sood S, Rosenbluh J, Kim JW, Zwang Y, Roberts TM, Root DE, Jacks T, Hahn WC (2014) KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 158:171–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, Group B-S (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30–39

    Article  PubMed  CAS  Google Scholar 

  113. Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, Asthana S, Neel D, Yan JJ, Lu X, Pham L, Wang MM, Karachaliou N, Cao MG, Manzano JL, Ramirez JL, Torres JM, Buttitta F, Rudin CM, Collisson EA, Algazi A, Robinson E, Osman I, Munoz-Couselo E, Cortes J, Frederick DT, Cooper ZA, McMahon M, Marchetti A, Rosell R, Flaherty KT, Wargo JA, Bivona TG (2015) The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 47:250–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kim MH, Kim J, Hong H, Lee SH, Lee JK, Jung E, Kim J (2016) Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J 35:462–478

    Article  CAS  PubMed  Google Scholar 

  115. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  CAS  PubMed  Google Scholar 

  116. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J (2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 373:726–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lee JE, Park HS, Lee D, Yoo G, Kim T, Jeon H, Yeo MK, Lee CS, Moon JY, Jung SS, Kim JO, Kim SY, Park DI, Park YH, Lee JC, Oh IJ, Lim DS, Chung C (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

    Article  CAS  PubMed  Google Scholar 

  118. Xu W, Wei Y, Wu S, Wang Y, Wang Z, Sun Y, Cheng SY, Wu J (2015) Up-regulation of the Hippo pathway effector TAZ renders lung adenocarcinoma cells harboring EGFR-T790 M mutation resistant to gefitinib. Cell Biosci 5:7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Lee KW, Lee SS, Kim SB, Sohn BH, Lee HS, Jang HJ, Park YY, Kopetz S, Kim SS, Oh SC, Lee JS (2015) Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients. Clin Cancer Res 21:357–364

    Article  CAS  PubMed  Google Scholar 

  120. Vici P, Mottolese M, Pizzuti L, Barba M, Sperati F, Terrenato I, Di Benedetto A, Natoli C, Gamucci T, Angelucci D, Ramieri MT, Di Lauro L, Sergi D, Bartucci M, Dattilo R, Pagliuca A, De Maria R, Maugeri-Sacca M (2014) The Hippo transducer TAZ as a biomarker of pathological complete response in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy. Oncotarget 5:9619–9625

    Article  PubMed  PubMed Central  Google Scholar 

  121. Lin CH, Pelissier FA, Zhang H, Lakins J, Weaver VM, Park C, LaBarge MA (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Huang JM, Nagatomo I, Suzuki E, Mizuno T, Kumagai T, Berezov A, Zhang H, Karlan B, Greene MI, Wang Q (2013) YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene 32:2220–2229

    Article  CAS  PubMed  Google Scholar 

  123. Akervall J, Nandalur S, Zhang J, Qian CN, Goldstein N, Gyllerup P, Gardinger Y, Alm J, Lorenc K, Nilsson K, Resau J, Wilson G, Teh B (2014) A novel panel of biomarkers predicts radioresistance in patients with squamous cell carcinoma of the head and neck. Eur J Cancer 50:570–581

    Article  CAS  PubMed  Google Scholar 

  124. Fernandez LA, Squatrito M, Northcott P, Awan A, Holland EC, Taylor MD, Nahle Z, Kenney AM (2012) Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene 31:1923–1937

    Article  CAS  Google Scholar 

  125. Tsujiura M, Mazack V, Sudol M, Kaspar HG, Nash J, Carey DJ, Gogoi R (2014) Yes-associated protein (YAP) modulates oncogenic features and radiation sensitivity in endometrial cancer. PLoS ONE 9:e100974

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Oh H, Slattery M, Ma L, Crofts A, White KP, Mann RS, Irvine KD (2013) Genome-wide association of Yorkie with chromatin and chromatin-remodeling complexes. Cell Rep 3:309–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Denduluri SK, Idowu O, Wang Z, Liao Z, Yan Z, Mohammed MK, Ye J, Wei Q, Wang J, Zhao L, Luu HH (2015) Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis 2:13–25

    Article  CAS  PubMed  Google Scholar 

  128. Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ, Richardson JA, Bassel-Duby R, Olson EN (2011) Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal 4:ra70

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Fan R, Kim NG, Gumbiner BM (2013) Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1. Proc Natl Acad Sci U S A 110:2569–2574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Strassburger K, Tiebe M, Pinna F, Breuhahn K, Teleman AA (2012) Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP. Dev Biol 367:187–196

    Article  CAS  PubMed  Google Scholar 

  131. Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL (2008) TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 28:2426–2436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Aylon Y, Michael D, Shmueli A, Yabuta N, Nojima H, Oren M (2006) A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev 20:2687–2700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ganem NJ, Cornils H, Chiu SY, O’Rourke KP, Arnaud J, Yimlamai D, Thery M, Camargo FD, Pellman D (2014) Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell 158:833–848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Furth N, Bossel Ben-Moshe N, Pozniak Y, Porat Z, Geiger T, Domany E, Aylon Y, Oren M (2015) Down-regulation of LATS kinases alters p53 to promote cell migration. Genes Dev 29:2325–2330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Di Agostino S, Sorrentino G, Ingallina E, Valenti F, Ferraiuolo M, Bicciato S, Piazza S, Strano S, Del Sal G, Blandino G (2016) YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins. EMBO Rep 17:188–201

    Article  PubMed  CAS  Google Scholar 

  136. Rosenbluh J, Nijhawan D, Cox AG, Li X, Neal JT, Schafer EJ, Zack TI, Wang X, Tsherniak A, Schinzel AC, Shao DD, Schumacher SE, Weir BA, Vazquez F, Cowley GS, Root DE, Mesirov JP, Beroukhim R, Kuo CJ, Goessling W, Hahn WC (2012) beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151:1457–1473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lee KK, Yonehara S (2012) Identification of mechanism that couples multisite phosphorylation of Yes-associated protein (YAP) with transcriptional coactivation and regulation of apoptosis. J Biol Chem 287:9568–9578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Yabuta N, Okada N, Ito A, Hosomi T, Nishihara S, Sasayama Y, Fujimori A, Okuzaki D, Zhao H, Ikawa M, Okabe M, Nojima H (2007) Lats2 is an essential mitotic regulator required for the coordination of cell division. J Biol Chem 282:19259–19271

    Article  CAS  PubMed  Google Scholar 

  139. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, Helfrich B, Dziadziuszko R, Chan DC, Sugita M, Chan Z, Baron A, Franklin W, Drabkin HA, Girard L, Gazdar AF, Minna JD, Bunn PA Jr (2006) Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 66:944–950

    Article  CAS  PubMed  Google Scholar 

  141. Sarkar FH, Li Y, Wang Z, Kong D (2009) Pancreatic cancer stem cells and EMT in drug resistance and metastasis. Minerva Chir 64:489–500

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Beverdam A, Claxton C, Zhang X, James G, Harvey KF, Key B (2013) Yap controls stem/progenitor cell proliferation in the mouse postnatal epidermis. J Invest Dermatol 133:1497–1505

    Article  CAS  PubMed  Google Scholar 

  143. Imajo M, Ebisuya M, Nishida E (2015) Dual role of YAP and TAZ in renewal of the intestinal epithelium. Nat Cell Biol 17:7–19

    Article  CAS  PubMed  Google Scholar 

  144. Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ, Camargo FD (2014) Hippo pathway activity influences liver cell fate. Cell 157:1324–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Skibinski A, Breindel JL, Prat A, Galvan P, Smith E, Rolfs A, Gupta PB, Labaer J, Kuperwasser C (2014) The Hippo transducer TAZ interacts with the SWI/SNF complex to regulate breast epithelial lineage commitment. Cell Rep 6:1059–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284

    Article  CAS  PubMed  Google Scholar 

  147. Abdullah LN, Chow EK (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2:3

    Article  PubMed  PubMed Central  Google Scholar 

  148. Fujimoto D, Ueda Y, Hirono Y, Goi T, Yamaguchi A (2015) PAR1 participates in the ability of multidrug resistance and tumorigenesis by controlling Hippo-YAP pathway. Oncotarget 6:34788–34799

    PubMed  PubMed Central  Google Scholar 

  149. Hong X, Nguyen HT, Chen Q, Zhang R, Hagman Z, Voorhoeve PM, Cohen SM (2014) Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover. EMBO J 33:2447–2457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Halder G, Dupont S, Piccolo S (2012) Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat Rev Mol Cell Biol 13:591–600

    Article  CAS  PubMed  Google Scholar 

  151. Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, Larkin J, Marais R, Sahai E (2015) Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 27:574–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Vici P, Ercolani C, Di Benedetto A, Pizzuti L, Di Lauro L, Sperati F, Terrenato I, Gamucci T, Natoli C, Di Filippo F, Botti C, Barba M, Mottolese M, De Maria R, Maugeri-Sacca M (2016) Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy. J Exp Clin Cancer Res 35:62

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Liu JY, Li YH, Lin HX, Liao YJ, Mai SJ, Liu ZW, Zhang ZL, Jiang LJ, Zhang JX, Kung HF, Zeng YX, Zhou FJ, Xie D (2013) Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder. BMC Cancer 13:349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Buglioni S, Vici P, Sergi D, Pizzuti L, Di Lauro L, Antoniani B, Sperati F, Terrenato I, Carosi M, Gamucci T, Vincenzoni C, Mariani L, Vizza E, Venuti A, Sanguineti G, Gadducci A, Barba M, Natoli C, Vitale I, Mottolese M, De Maria R, Maugeri-Sacca M (2016) Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment. Oncoimmunology 5:e1160187

    Article  PubMed  CAS  Google Scholar 

  155. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, Liu JO, Pan D (2012) Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 26:1300–1305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X, He F, Wang Y, Zhang Z, Wang W, Wang X, Guo T, Li P, Zhao Y, Ji H, Zhang L, Zhou Z (2014) A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25:166–180

    Article  CAS  PubMed  Google Scholar 

  157. Zhang W, Gao Y, Li P, Shi Z, Guo T, Li F, Han X, Feng Y, Zheng C, Wang Z, Li F, Chen H, Zhou Z, Zhang L, Ji H (2014) VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res 24:331–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Poon CL, Zhang X, Lin JI, Manning SA, Harvey KF (2012) Homeodomain-interacting protein kinase regulates Hippo pathway-dependent tissue growth. Curr Biol 22:1587–1594

    Article  CAS  PubMed  Google Scholar 

  159. Chen J, Verheyen EM (2012) Homeodomain-interacting protein kinase regulates Yorkie activity to promote tissue growth. Curr Biol 22:1582–1586

    Article  CAS  PubMed  Google Scholar 

  160. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN, Acerbi I, Ou G, Wijekoon AC, Levental KR, Gilbert PM, Hwang ES, Chen YY, Weaver VM (2014) Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat Med 20:360–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Gronich N, Rennert G (2013) Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol 10:625–642

    Article  CAS  PubMed  Google Scholar 

  163. Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, Fang Z, Zhao K, Konaparthi R, Hua S, Zhang J, Li-Ning-Tapia EM, Kapoor A, Wu CJ, Patel NB, Guo Z, Ramamoorthy V, Tieu TN, Heffernan T, Zhao D, Shang X, Khadka S, Hou P, Hu B, Jin EJ, Yao W, Pan X, Ding Z, Shi Y, Li L, Chang Q, Troncoso P, Logothetis CJ, McArthur MJ, Chin L, Wang YA, DePinho RA (2016) Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov 6:80–95

    Article  CAS  PubMed  Google Scholar 

  164. Du X, Yu A, Tao W (2015) The non-canonical Hippo/Mst pathway in lymphocyte development and functions. Acta Biochim Biophys Sin 47:60–64

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Basic Core Technology Development Program of the National Research Foundation funded by the Korean Ministry of Science, ICT and Future Planning (2016903757).

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    Min Hwan Kim & Joon Kim

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Kim, M.H., Kim, J. Role of YAP/TAZ transcriptional regulators in resistance to anti-cancer therapies. Cell. Mol. Life Sci. 74, 1457–1474 (2017). https://doi.org/10.1007/s00018-016-2412-x

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