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Multilayer control of the EMT master regulators

Oncogene volume 33, pages 1755–1763 (2014)Cite this article

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Abstract

Metastasis is the leading cause of cancer-associated death in most tumor types. Metastatic dissemination of cancer cells from the primary tumor is believed to be initiated by the reactivation of an embryonic development program referred to as epithelial–mesenchymal transition (EMT), whereby epithelial cells lose apicobasal polarity and cell–cell contacts, and gain mesenchymal phenotypes with increased migratory and invasive capabilities. EMT has also been implicated in the regulation of cancer stem cell property, immune suppression and cancer regression. Several transcription factors have been identified as master regulators of EMT, including the Snail, Zeb and Twist families, and their expression is tightly regulated at different steps of transcription, translation and protein stability control by a variety of cell-intrinsic pathways as well as extracellular cues. Here, we review the recent literature on the signaling pathways and mechanisms that control the expression of these master transcription factors during EMT and cancer progression.

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References

  1. Chambers AF, Groom AC, MacDonald IC . Dissemination and growth of cancer cells in metastatic sites. Nat Rev 2002; 2: 563–572.

    CAS  Google Scholar 

  2. Nguyen DX, Bos PD, Massague J . Metastasis: from dissemination to organ-specific colonization. Nat Rev 2009; 9: 274–284.

    CAS  Google Scholar 

  3. Valastyan S, Weinberg RA . Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275–292.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Fidler IJ . The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev 2003; 3: 453–458.

    CAS  Google Scholar 

  5. Sethi N, Kang Y . Unravelling the complexity of metastasis—molecular understanding and targeted therapies. Nat Rev 2011; 11: 735–748.

    CAS  Google Scholar 

  6. Friedl P, Alexander S . Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 2011; 147: 992–1009.

    CAS  PubMed  Google Scholar 

  7. Yang J, Weinberg RA . Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818–829.

    CAS  PubMed  Google Scholar 

  8. Thiery JP, Acloque H, Huang RY, Nieto MA . Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139: 871–890.

    CAS  PubMed  Google Scholar 

  9. Nieto MA . The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 2011; 27: 347–376.

    CAS  PubMed  Google Scholar 

  10. Kang Y, Massague J . Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004; 118: 277–279.

    CAS  PubMed  Google Scholar 

  11. Acloque H, Ocana OH, Matheu A, Rizzoti K, Wise C, Lovell-Badge R et al. Reciprocal repression between Sox3 and snail transcription factors defines embryonic territories at gastrulation. Dev Cell 2011; 21: 546–558.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Thompson EW, Williams ED . EMT and MET in carcinoma–clinical observations, regulatory pathways and new models. Clin Exp Metastasis 2008; 25: 591–592.

    PubMed  Google Scholar 

  13. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117: 927–939.

    CAS  PubMed  Google Scholar 

  14. Tarin D, Thompson EW, Newgreen DF . The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 2005; 65: 5996–6000 discussion-1.

    CAS  PubMed  Google Scholar 

  15. Thompson EW, Newgreen DF, Tarin D . Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res 2005; 65: 5991–5995 discussion 5.

    CAS  PubMed  Google Scholar 

  16. Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 2001; 98: 10356–10361.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Franci C, Takkunen M, Dave N, Alameda F, Gomez S, Rodriguez R et al. Expression of Snail protein in tumor-stroma interface. Oncogene 2006; 25: 5134–5144.

    CAS  PubMed  Google Scholar 

  18. Huang D, Du X . Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination. World J Gastroenterol 2008; 14: 1823–1827.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Thiery JP . Epithelial-mesenchymal transitions in tumour progression. Nat Rev 2002; 2: 442–454.

    CAS  Google Scholar 

  20. Voulgari A, Pintzas A . Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta 2009; 1796: 75–90.

    CAS  PubMed  Google Scholar 

  21. Brabletz T . To differentiate or not–routes towards metastasis. Nat Rev 2012; 12: 425–436.

    CAS  Google Scholar 

  22. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J . Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 2012; 22: 725–736.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Barr S, Thomson S, Buck E, Russo S, Petti F, Sujka-Kwok I et al. Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clin Exp Metastasis 2008; 25: 685–693.

    PubMed Central  PubMed  Google Scholar 

  25. Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA . Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004; 18: 1131–1143.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Mejlvang J, Kriajevska M, Vandewalle C, Chernova T, Sayan AE, Berx G et al. Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial mesenchymal transition. Mol Biol Cell 2007; 18: 4615–4624.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Jung A, Schrauder M, Oswald U, Knoll C, Sellberg P, Palmqvist R et al. The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am J Pathol 2001; 159: 1613–1617.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Graff JR, Gabrielson E, Fujii H, Baylin SB, Herman JG . Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J Biol Chem 2000; 275: 2727–2732.

    CAS  PubMed  Google Scholar 

  29. Jeschke U, Mylonas I, Kuhn C, Shabani N, Kunert-Keil C, Schindlbeck C et al. Expression of E-cadherin in human ductal breast cancer carcinoma in situ, invasive carcinomas, their lymph node metastases, their distant metastases, carcinomas with recurrence and in recurrence. Anticancer Res 2007; 27: 1969–1974.

    CAS  PubMed  Google Scholar 

  30. Park D, Karesen R, Axcrona U, Noren T, Sauer T . Expression pattern of adhesion molecules (E-cadherin, alpha-, beta-, gamma-catenin and claudin-7), their influence on survival in primary breast carcinoma, and their corresponding axillary lymph node metastasis. APMIS 2007; 115: 52–65.

    CAS  PubMed  Google Scholar 

  31. Chao YL, Shepard CR, Wells A . Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 2010; 9: 179.

    PubMed Central  PubMed  Google Scholar 

  32. Ocana OH, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 2012; 22: 709–724.

    CAS  PubMed  Google Scholar 

  33. Celia-Terrassa T, Meca-Cortes O, Mateo F, de Paz AM, Rubio N, Arnal-Estape A et al. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Investig 2012; 122: 1849–1868.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celia-Terrassa T et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 2011; 17: 1101–1108.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED . Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res 2006; 66: 11271–11278.

    CAS  PubMed  Google Scholar 

  36. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148: 349–361.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Polyak K, Metzger Filho O . SnapShot: breast cancer. Cancer Cell 2012; 22: 562–562.e1.

    CAS  PubMed  Google Scholar 

  38. Peinado H, Olmeda D, Cano A Snail . Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7: 415–428.

    Article  CAS  PubMed  Google Scholar 

  39. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2: 84–89.

    Article  CAS  PubMed  Google Scholar 

  40. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76–83.

    CAS  PubMed  Google Scholar 

  41. Hajra KM, Chen DY, Fearon ER . The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 2002; 62: 1613–1618.

    CAS  PubMed  Google Scholar 

  42. Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 2005; 24: 2375–2385.

    CAS  PubMed  Google Scholar 

  43. Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 2001; 7: 1267–1278.

    CAS  PubMed  Google Scholar 

  44. Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, Andersen H et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res 2005; 33: 6566–6578.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Hartwell KA, Muir B, Reinhardt F, Carpenter AE, Sgroi DC, Weinberg RA . The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc Natl Acad Sci USA 2006; 103: 18969–18974.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA. 2007; 104: 10069–10074.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang H, Meng F, Liu G, Zhang B, Zhu J, Wu F et al. Forkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis. Cancer Res 2011; 71: 1292–1301.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Wang X, Zheng M, Liu G, Xia W, McKeown-Longo PJ, Hung MC et al. Kruppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res 2007; 67: 7184–7193.

    CAS  PubMed  Google Scholar 

  49. Peinado H, Quintanilla M, Cano A . Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 2003; 278: 21113–21123.

    CAS  PubMed  Google Scholar 

  50. Romano LA, Runyan RB . Slug is an essential target of TGFbeta2 signaling in the developing chicken heart. Dev Biol 2000; 223: 91–102.

    CAS  PubMed  Google Scholar 

  51. Thuault S, Tan EJ, Peinado H, Cano A, Heldin CH, Moustakas A . HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem 2008; 283: 33437–33446.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM, Diez J et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 2004; 18: 99–115.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U . Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 2008; 105: 6392–6397.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM . Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol 2005; 168: 29–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004; 6: 931–940.

    CAS  PubMed  Google Scholar 

  56. Zhou BP, Hung MC . Wnt, hedgehog and snail: sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis. Cell Cycle 2005; 4: 772–776.

    CAS  PubMed  Google Scholar 

  57. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 2005; 436: 123–127.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol 2003; 163: 1437–1447.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Lester RD, Jo M, Montel V, Takimoto S, Gonias SL . uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol 2007; 178: 425–436.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Lopez-Novoa JM, Nieto MA . Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 2009; 1: 303–314.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Copple BL . Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms. Liver Int 2010; 30: 669–682.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Liu YN, Abou-Kheir W, Yin JJ, Fang L, Hynes P, Casey O et al. Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor beta-initiated prostate cancer epithelial-mesenchymal transition. Mol Cell Biol 2012; 32: 941–953.

    PubMed Central  PubMed  Google Scholar 

  63. Liu YN, Yin JJ, Abou-Kheir W, Hynes PG, Casey OM, Fang L et al. MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene 2012; 32: 296–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Laffin B, Wellberg E, Kwak HI, Burghardt RC, Metz RP, Gustafson T et al. Loss of singleminded-2s in the mouse mammary gland induces an epithelial-mesenchymal transition associated with up-regulation of slug and matrix metalloprotease 2. Mol Cell Biol 2008; 28: 1936–1946.

    CAS  PubMed  Google Scholar 

  65. Chakrabarti R, Hwang J, Andres Blanco M, Wei Y, Lukacisin M, Romano RA et al. Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat Cell Biol 2012; 14: 1212–1222.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Guo W, Keckesova Z, Donaher JL, Shibue T, Tischler V, Reinhardt F et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 2012; 148: 1015–1028.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Hu J, Guo H, Li H, Liu Y, Liu J, Chen L et al. MiR-145 regulates epithelial to mesenchymal transition of breast cancer cells by targeting Oct4. PLoS One 2012; 7: e45965.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Kim NH, Kim HS, Li XY, Lee I, Choi HS, Kang SE et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J Cell Biol 2011; 195: 417–433.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Nalls D, Tang SN, Rodova M, Srivastava RK, Shankar S . Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One 2011; 6: e24099.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Siemens H, Jackstadt R, Hunten S, Kaller M, Menssen A, Gotz U et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 2011; 10: 4256–4271.

    CAS  PubMed  Google Scholar 

  71. Kumarswamy R, Mudduluru G, Ceppi P, Muppala S, Kozlowski M, Niklinski J et al. MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer. Int J Cancer 2012; 130: 2044–2053.

    CAS  PubMed  Google Scholar 

  72. Wang FE, Zhang C, Maminishkis A, Dong L, Zhi C, Li R et al. MicroRNA-204/211 alters epithelial physiology. FASEB J 2010; 24: 1552–1571.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Liu S, Kumar SM, Lu H, Liu A, Yang R, Pushparajan A et al. MicroRNA-9 up-regulates E-cadherin through inhibition of NF-kappaB1-Snail1 pathway in melanoma. J Pathol 2012; 226: 61–72.

    CAS  PubMed  Google Scholar 

  74. Chang CJ, Hsu CC, Chang CH, Tsai LL, Chang YC, Lu SW et al. Let-7d functions as novel regulator of epithelial-mesenchymal transition and chemoresistant property in oral cancer. Oncol Rep 2011; 26: 1003–1010.

    CAS  PubMed  Google Scholar 

  75. Lee MR, Kim JS, Kim KS . miR-124a is important for migratory cell fate transition during gastrulation of human embryonic stem cells. Stem Cells 2010; 28: 1550–1559.

    CAS  PubMed  Google Scholar 

  76. Xia H, Cheung WK, Ng SS, Jiang X, Jiang S, Sze J et al. Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells. J Biol Chem 2012; 287: 9962–9971.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Zhang Z, Zhang B, Li W, Fu L, Zhu Z, Dong JT . Epigenetic Silencing of miR-203 upregulates SNAI2 and contributes to the invasiveness of malignant breast cancer cells. Genes Cancer 2011; 2: 782–791.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Lander R, Nordin K, LaBonne C . The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1. J Cell Biol 2011; 194: 17–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Vernon AE, LaBonne C . Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa. Development 2006; 133: 3359–3370.

    CAS  PubMed  Google Scholar 

  80. Hubbard EJ, Wu G, Kitajewski J, Greenwald I . sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Genes Dev 1997; 11: 3182–3193.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J 2004; 23: 2116–2125.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Welcker M, Orian A, Jin J, Grim JE, Harper JW, Eisenman RN et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA 2004; 101: 9085–9090.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Welcker M, Orian A, Grim JE, Eisenman RN, Clurman BE . A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size. Curr Biol 2004; 14: 1852–1857.

    CAS  PubMed  Google Scholar 

  84. Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 2001; 294: 173–177.

    CAS  PubMed  Google Scholar 

  85. Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG Jr. . The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 2005; 8: 25–33.

    CAS  PubMed  Google Scholar 

  86. Zhao D, Zheng HQ, Zhou Z, Chen C . The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses breast cell proliferation. Cancer Res 2010; 70: 4728–4738.

    CAS  PubMed  Google Scholar 

  87. Liu N, Li H, Li S, Shen M, Xiao N, Chen Y et al. The Fbw7/human CDC4 tumor suppressor targets proproliferative factor KLF5 for ubiquitination and degradation through multiple phosphodegron motifs. J Biol Chem 2010; 285: 18858–18867.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Gupta-Rossi N, Le Bail O, Gonen H, Brou C, Logeat F, Six E et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. J Biol Chem 2001; 276: 34371–34378.

    CAS  PubMed  Google Scholar 

  89. Vinas-Castells R, Beltran M, Valls G, Gomez I, Garcia JM, Montserrat-Sentis B et al. The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. J Biol Chem 2010; 285: 3794–3805.

    CAS  PubMed  Google Scholar 

  90. Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH et al. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol 2006; 8: 1398–1406.

    CAS  PubMed  Google Scholar 

  91. Zhang K, Rodriguez-Aznar E, Yabuta N, Owen RJ, Mingot JM, Nojima H et al. Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation. EMBO J 2012; 31: 29–43.

    PubMed  Google Scholar 

  92. Yang Z, Rayala S, Nguyen D, Vadlamudi RK, Chen S, Kumar R . Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res 2005; 65: 3179–3184.

    CAS  PubMed  Google Scholar 

  93. Pon YL, Zhou HY, Cheung AN, Ngan HY, Wong AS . p70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cells. Cancer Res 2008; 68: 6524–6532.

    CAS  PubMed  Google Scholar 

  94. Du C, Zhang C, Hassan S, Biswas MH, Balaji KC . Protein kinase D1 suppresses epithelial-to-mesenchymal transition through phosphorylation of snail. Cancer Res 2010; 70: 7810–7819.

    CAS  PubMed  Google Scholar 

  95. Bastea LI, Doppler H, Balogun B, Storz P . Protein kinase D1 maintains the epithelial phenotype by inducing a DNA-bound, inactive SNAI1 transcriptional repressor complex. PLoS One 2012; 7: e30459.

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Eiseler T, Kohler C, Nimmagadda SC, Jamali A, Funk N, Joodi G et al. Protein kinase D1 mediates anchorage-dependent and -independent growth of tumor cells via the zinc finger transcription factor Snail1. J Biol Chem 2012; 287: 32367–32380.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Wu ZQ, Li XY, Hu CY, Ford M, Kleer CG, Weiss SJ . Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression. Proc Natl Acad Sci USA 2012; 109: 16654–16659.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009; 138: 645–659.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y . Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 2009; 15: 195–206.

    CAS  PubMed  Google Scholar 

  100. Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 2005; 8: 197–209.

    CAS  PubMed  Google Scholar 

  101. Hebrok M, Wertz K, Fuchtbauer EM . M-twist is an inhibitor of muscle differentiation. Dev Biol 1994; 165: 537–544.

    CAS  PubMed  Google Scholar 

  102. Chen ZF, Behringer RR . Twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev 1995; 9: 686–699.

    CAS  PubMed  Google Scholar 

  103. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N et al. A twist code determines the onset of osteoblast differentiation. Dev Cell 2004; 6: 423–435.

    CAS  PubMed  Google Scholar 

  104. Casas E, Kim J, Bendesky A, Ohno-Machado L, Wolfe CJ, Yang J . Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res 2011; 71: 245–254.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Eckert MA, Lwin TM, Chang AT, Kim J, Danis E, Ohno-Machado L et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell 2011; 19: 372–386.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 2008; 14: 79–89.

    CAS  PubMed  Google Scholar 

  107. Tsuji T, Ibaragi S, Shima K, Hu MG, Katsurano M, Sasaki A et al. Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Res 2008; 68: 10377–10386.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 2010; 12: 982–992.

    PubMed  Google Scholar 

  109. Ma L, Teruya-Feldstein J, Weinberg RA . Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007; 449: 682–688.

    CAS  PubMed  Google Scholar 

  110. Yang WH, Lan HY, Huang CH, Tai SK, Tzeng CH, Kao SY et al. RAC1 activation mediates Twist1-induced cancer cell migration. Nat Cell Biol 2012; 14: 366–374.

    CAS  PubMed  Google Scholar 

  111. Clark EA, Golub TR, Lander ES, Hynes RO . Genomic analysis of metastasis reveals an essential role for RhoC. Nature 2000; 406: 532–535.

    CAS  PubMed  Google Scholar 

  112. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399: 271–275.

    CAS  PubMed  Google Scholar 

  113. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ et al. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 2008; 10: 295–305.

    CAS  PubMed  Google Scholar 

  114. Ryan HE, Lo J, Johnson RS . HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 1998; 17: 3005–3156.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 1998; 12: 149–162.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS . Stem cells in normal breast development and breast cancer. Cell Prolif 2003; 36 (Suppl 1): 59–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. El-Haibi CP, Bell GW, Zhang J, Collmann AY, Wood D, Scherber CM et al. Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proc Natl Acad Sci USA 2012; 109: 17460–17465.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Li B, Han Q, Zhu Y, Yu Y, Wang J, Jiang X . Down-regulation of miR-214 contributes to intrahepatic cholangiocarcinoma metastasis by targeting Twist. FEBS J 2012; 279: 2393–2398.

    CAS  PubMed  Google Scholar 

  120. Nairismagi ML, Vislovukh A, Meng Q, Kratassiouk G, Beldiman C, Petretich M et al. Translational control of TWIST1 expression in MCF-10A cell lines recapitulating breast cancer progression. Oncogene 2012; 31: 4960–4966.

    PubMed  Google Scholar 

  121. Yin G, Alvero AB, Craveiro V, Holmberg JC, Fu HH, Montagna MK et al. Constitutive proteasomal degradation of TWIST-1 in epithelial-ovarian cancer stem cells impacts differentiation and metastatic potential. Oncogene 2013; 32: 39–49.

    CAS  PubMed  Google Scholar 

  122. Hong J, Zhou J, Fu J, He T, Qin J, Wang L et al. Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res 2011; 71: 3980–3990.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H et al. Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet 2001; 27: 369–370.

    CAS  PubMed  Google Scholar 

  124. Liskova P, Tuft SJ, Gwilliam R, Ebenezer ND, Jirsova K, Prescott Q et al. Novel mutations in the ZEB1 gene identified in Czech and British patients with posterior polymorphous corneal dystrophy. Hum Mutat 2007; 28: 638.

    PubMed Central  PubMed  Google Scholar 

  125. Van de Putte T, Maruhashi M, Francis A, Nelles L, Kondoh H, Huylebroeck D et al. Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease-mental retardation syndrome. Am J Hum Genet 2003; 72: 465–470.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Imamichi Y, Konig A, Gress T, Menke A . Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer. Oncogene 2007; 26: 2381–2385.

    CAS  PubMed  Google Scholar 

  127. Maeda G, Chiba T, Okazaki M, Satoh T, Taya Y, Aoba T et al. Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol 2005; 27: 1535–1541.

    CAS  PubMed  Google Scholar 

  128. Spaderna S, Schmalhofer O, Hlubek F, Berx G, Eger A, Merkel S et al. A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology 2006; 131: 830–840.

    CAS  PubMed  Google Scholar 

  129. Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A et al. The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res 2008; 68: 537–544.

    CAS  PubMed  Google Scholar 

  130. Spoelstra NS, Manning NG, Higashi Y, Darling D, Singh M, Shroyer KR et al. The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers. Cancer Res 2006; 66: 3893–3902.

    CAS  PubMed  Google Scholar 

  131. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 2009; 11: 1487–1495.

    CAS  PubMed  Google Scholar 

  132. Remacle JE, Kraft H, Lerchner W, Wuytens G, Collart C, Verschueren K et al. New mode of DNA binding of multi-zinc finger transcription factors: deltaEF1 family members bind with two hands to two target sites. EMBO J 1999; 18: 5073–5084.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y et al. Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer 2004; 90: 1265–1273.

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Taki M, Verschueren K, Yokoyama K, Nagayama M, Kamata N . Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Int J Oncol 2006; 28: 487–496.

    CAS  PubMed  Google Scholar 

  135. Karreth FA, Tay Y, Perna D, Ala U, Tan SM, Rust AG et al. In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 2011; 147: 382–395.

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH et al. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res 2006; 66: 2725–2731.

    CAS  PubMed  Google Scholar 

  137. Arima Y, Hayashi H, Sasaki M, Hosonaga M, Goto TM, Chiyoda T et al. Induction of ZEB proteins by inactivation of RB protein is key determinant of mesenchymal phenotype of breast cancer. J Biol Chem 2012; 287: 7896–7906.

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Cieply B, Pt Riley, Pifer PM, Widmeyer J, Addison JB, Ivanov AV et al. Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2. Cancer Res 2012; 72: 2440–2453.

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Long J, Zuo D, Park M . Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin. J Biol Chem 2005; 280: 35477–35489.

    CAS  PubMed  Google Scholar 

  140. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 2008; 9: 582–589.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008; 10: 593–601.

    CAS  PubMed  Google Scholar 

  142. Korpal M, Lee ES, Hu G, Kang Y . The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 2008; 283: 14910–14914.

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Park SM, Gaur AB, Lengyel E, Peter ME . The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 2008; 22: 894–907.

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 2008; 68: 7846–7854.

    CAS  PubMed  Google Scholar 

  145. Liu X, Wang C, Chen Z, Jin Y, Wang Y, Kolokythas A et al. MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines. Biochem J 2011; 440: 23–31.

    CAS  PubMed  Google Scholar 

  146. Saini S, Majid S, Yamamura S, Tabatabai L, Suh SO, Shahryari V et al. Regulatory role of mir-203 in prostate cancer progression and metastasis. Clin Cancer Res 2011; 17: 5287–5298.

    CAS  PubMed  Google Scholar 

  147. White NM, Khella HW, Grigull J, Adzovic S, Youssef YM, Honey RJ et al. miRNA profiling in metastatic renal cell carcinoma reveals a tumour-suppressor effect for miR-215. Br J Cancer 2011; 105: 1741–1749.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Saini S, Yamamura S, Majid S, Shahryari V, Hirata H, Tanaka Y et al. MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells. Cancer Res 2011; 71: 6208–6219.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Thompson EW, Haviv I . The social aspects of EMT-MET plasticity. Nat Med 2011; 17: 1048–1049.

    CAS  PubMed  Google Scholar 

  150. Brabletz T . EMT and MET in metastasis: where are the cancer stem cells? Cancer Cell 2012; 22: 699–701.

    CAS  PubMed  Google Scholar 

  151. Krupa A, Jenkins R, Luo DD, Lewis A, Phillips A, Fraser D . Loss of MicroRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol 2010; 21: 438–447.

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Jenkins RH, Martin J, Phillips AO, Bowen T, Fraser DJ . Pleiotropy of microRNA-192 in the kidney. Biochem Soc Trans 2012; 40: 762–767.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to researchers whose studies we were unable to cite due to the space limitation of this review. We thank W Li and HA Smith for reading the manuscript and providing insightful advises. Research in our laboratory is supported by grants from the National Institutes of Health R01CA134519 and R01CA141062, Komen for the Cure, the Brewster Foundation and the Champalimaud Foundation. H Zheng is a recipient of a Komen for the Cure Postdoctoral Fellowship (KG111164).

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  1. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    H Zheng & Y Kang

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Zheng, H., Kang, Y. Multilayer control of the EMT master regulators. Oncogene 33, 1755–1763 (2014). https://doi.org/10.1038/onc.2013.128

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