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Non-redundant functions of EMT transcription factors

Nature Cell Biology volume 21, pages 102–112 (2019)Cite this article

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Abstract

Epithelial–mesenchymal transition (EMT) is a crucial embryonic programme that is executed by various EMT transcription factors (EMT-TFs) and is aberrantly activated in cancer and other diseases. However, the causal role of EMT and EMT-TFs in different disease processes, especially cancer and metastasis, continues to be debated. In this Review, we identify and describe specific, non-redundant functions of the different EMT-TFs and discuss the reasons that may underlie disputes about EMT in cancer.

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Fig. 1: Overview of EMT-TF properties and protein structures.
Fig. 2: Differential expression and function of EMT-TFs in cancer.

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References

  1. Nieto, M. A., Huang, R. Y.-J., Jackson, R. A. & Thiery, J. P. EMT: 2016. Cell 166, 21–45 (2016).

    CAS  PubMed  Google Scholar 

  2. Puisieux, A., Brabletz, T. & Caramel, J. Oncogenic roles of EMT-inducing transcription factors. Nat. Cell Biol. 16, 488–494 (2014).

    CAS  PubMed  Google Scholar 

  3. Huang, R. & Zong, X. Aberrant cancer metabolism in epithelial–mesenchymal transition and cancer metastasis: mechanisms in cancer progression. Crit. Rev. Oncol. Hematol. 115, 13–22 (2017).

    PubMed  Google Scholar 

  4. Sciacovelli, M. & Frezza, C. Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J. 284, 3132–3144 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Brabletz, T. To differentiate or not—routes towards metastasis. Nat. Rev. Cancer 12, 425–436 (2012).

    CAS  PubMed  Google Scholar 

  6. Nieto, M. A. & Cano, A. The epithelial–mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin. Cancer Biol. 22, 361–368 (2012).

    CAS  PubMed  Google Scholar 

  7. Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).

    PubMed  Google Scholar 

  8. Varga, J. & Greten, F. R. Cell plasticity in epithelial homeostasis and tumorigenesis. Nat. Cell Biol. 19, 1133–1141 (2017).

    CAS  PubMed  Google Scholar 

  9. Ledford, H. Cancer theory faces doubts. Nature 472, 273 (2011).

    CAS  PubMed  Google Scholar 

  10. Tarin, D., Thompson, E. W. & Newgreen, D. F. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 65, 5996–6000 (2005).

    CAS  PubMed  Google Scholar 

  11. Friedl, P. & Gilmour, D. Collective cell migration in morphogenesis, regeneration and cancer. Nat. Rev. Mol. Cell Biol. 10, 445–457 (2009).

    CAS  PubMed  Google Scholar 

  12. Bronsert, P. et al. Cancer cell invasion and EMT marker expression—a three-dimensional study of the human cancer–host interface. J. Pathol. 234, 410–422 (2014).

    CAS  PubMed  Google Scholar 

  13. Enderle-Ammour, K. et al. Form follows function: morphological and immunohistological insights into epithelial–mesenchymal transition characteristics of tumor buds. Tumor Biol. 39, 1–11 (2017).

    Google Scholar 

  14. Aiello, N. M. et al. Upholding a role for EMT in pancreatic cancer metastasis. Nature 547, E7–E8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Brabletz, T., Kalluri, R., Nieto, M. A. & Weinberg, R. A. EMT in cancer. Nat. Rev. Cancer 18, 128–134 (2018).

    CAS  PubMed  Google Scholar 

  16. Maheswaran, S. & Haber, D. A. Transition loses its invasive edge. Nature 527, 452–453 (2015).

    CAS  PubMed  Google Scholar 

  17. Ruben, B. & Gerhard, C. The relevance of EMT in breast cancer metastasis: correlation or causality? FEBS Lett. 589, 1577–1587 (2015).

    Google Scholar 

  18. Santamaria, P. G., Moreno‐Bueno, G., Portillo, F. & Cano, A. EMT: present and future in clinical oncology. Mol. Oncol. 11, 718–738 (2017).

    PubMed  PubMed Central  Google Scholar 

  19. Ye, X. et al. Upholding a role for EMT in breast cancer metastasis. Nature 547, E1–E3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zheng, X. et al. Epithelial-to-mesen10chymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Krebs, A. M. et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19, 518–529 (2017).

    CAS  PubMed  Google Scholar 

  23. Ni, T. et al. Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer. Nat. Cell Biol. 18, 1221–1232 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tran, H. D. et al. Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. Cancer Res. 74, 6330–6340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Xu, Y. et al. Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice. Proc. Natl Acad. Sci. USA 114, 11494–11499 (2017).

    CAS  PubMed  Google Scholar 

  26. Goossens, S., Vandamme, N., Van Vlierberghe, P. & Berx, G. EMT transcription factors in cancer development re-evaluated: beyond EMT and MET. Biochim. Biophys. Acta 1868, 584–591 (2017).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Diepenbruck, M. et al. Tead2 expression levels control the subcellular distribution of Yap and Taz, zyxin expression and epithelial–mesenchymal transition. J. Cell Sci. 127, 1523–1536 (2014).

    CAS  PubMed  Google Scholar 

  29. Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lehmann, W. et al. ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types. Nat. Commun. 7, 10498 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mani, S. A. 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 104, 10069–10074 (2007).

    CAS  PubMed  Google Scholar 

  32. Ocaña, O. H. et al. Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).

    PubMed  Google Scholar 

  33. Perez-Moreno, M. A. et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial–mesenchymal transitions. J. Biol. Chem. 276, 27424–27431 (2001).

    CAS  PubMed  Google Scholar 

  34. Tiwari, N. et al. Sox4 is a master regulator of epithelial–mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell 23, 768–783 (2013).

    CAS  PubMed  Google Scholar 

  35. Skrypek, N., Goossens, S., De Smedt, E., Vandamme, N. & Berx, G. Epithelial-to-mesenchymal transition: epigenetic reprogramming driving cellular plasticity. Trends Genet. 33, 943–959 (2017).

    CAS  PubMed  Google Scholar 

  36. Díaz, V. M. & de Herreros, A. G. F-box proteins: keeping the epithelial-to-mesenchymal transition (EMT) in check. Semin. Cancer Biol. 36, 71–79 (2016).

    PubMed  Google Scholar 

  37. Nieto, M. A. The Snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell Biol. 3, 155–166 (2002).

    CAS  PubMed  Google Scholar 

  38. Caramel, J. et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24, 466–480 (2013).

    CAS  PubMed  Google Scholar 

  39. Denecker, G. et al. Identification of a ZEB2–MITF–ZEB1 transcriptional network that controls melanogenesis and melanoma progression. Cell Death Differ. 21, 1250–1261 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Tulchinsky, E., Pringle, J. H., Caramel, J. & Ansieau, S. Plasticity of melanoma and EMT-TF reprogramming. Oncotarget 5, 1–2 (2014).

    PubMed  Google Scholar 

  41. Richard, G. et al. ZEB1‐mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Mol. Med. 8, 1143–1161 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mejlvang, J. et al. Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial mesenchymal transition. Mol. Biol. Cell 18, 4615–4624 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Gubelmann, C. et al. Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network. eLife 3, e03346 (2014).

    PubMed  PubMed Central  Google Scholar 

  44. Mathow, D. et al. Zeb1 affects epithelial cell adhesion by diverting glycosphingolipid metabolism. EMBO Rep. 16, 321–331 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Postigo, A. A. Opposing functions of ZEB proteins in the regulation of the TGFβ/BMP signaling pathway. EMBO J. 22, 2443–2452 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Gheldof, A., Hulpiau, P., van Roy, F., De Craene, B. & Berx, G. Evolutionary functional analysis and molecular regulation of the ZEB transcription factors. Cell. Mol. Life Sci. 69, 2527–2541 (2012).

    CAS  PubMed  Google Scholar 

  48. Postigo, A. A., Depp, J. L., Taylor, J. J. & Kroll, K. L. Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins. EMBO J. 22, 2453–2462 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sefton, M., Sanchez, S. & Nieto, M. A. Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. Development 125, 3111–3121 (1998).

    CAS  PubMed  Google Scholar 

  50. Carver, E. A., Jiang, R., Lan, Y., Oram, K. F. & Gridley, T. The mouse Snail gene encodes a key regulator of the epithelial–mesenchymal transition. Mol. Cell. Biol. 21, 8184–8188 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Murray, S. A. & Gridley, T. Snail family genes are required for left–right asymmetry determination, but not neural crest formation, in mice. Proc. Natl Acad. Sci. USA 103, 10300–10304 (2006).

    CAS  PubMed  Google Scholar 

  52. Soo, K. et al. Twist function is required for the morphogenesis of the cephalic neural tube and the differentiation of the cranial neural crest cells in the mouse embryo. Dev. Biol. 247, 251–270 (2002).

    CAS  PubMed  Google Scholar 

  53. Van de Putte, T. 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. 72, 465–470 (2003).

    PubMed  PubMed Central  Google Scholar 

  54. Chen, Z. F. & Behringer, R. R. Twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 9, 686–699 (1995).

    CAS  PubMed  Google Scholar 

  55. Miyoshi, T. et al. Complementary expression pattern of Zfhx1 genes Sip1 and δEF1 in the mouse embryo and their genetic interaction revealed by compound mutants. Dev. Dyn. 235, 1941–1952 (2006).

    CAS  PubMed  Google Scholar 

  56. Brabletz, S. et al. Generation and characterization of mice for conditional inactivation of Zeb1. Genesis 55, e23024 (2017).

    Google Scholar 

  57. Takagi, T., Moribe, H., Kondoh, H. & Higashi, Y. DeltaEF1, a zinc finger and homeodomain transcription factor, is required for skeleton patterning in multiple lineages. Development 125, 21–31 (1998).

    CAS  PubMed  Google Scholar 

  58. Murray, S. A., Carver, E. A. & Gridley, T. Generation of a Snail1 (Snai1) conditional null allele. Genesis 44, 7–11 (2006).

    CAS  PubMed  Google Scholar 

  59. Ocaña, O. H. et al. A right-handed signalling pathway drives heart looping in vertebrates. Nature 549, 86–90 (2017).

    PubMed  PubMed Central  Google Scholar 

  60. Chen, Y. & Gridley, T. Compensatory regulation of the Snai1 and Snai2 genes during chondrogenesis. J. Bone Miner. Res. 28, 1412–1421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Dale, J. K. et al. Oscillations of the Snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis. Dev. Cell 10, 355–366 (2006).

    CAS  PubMed  Google Scholar 

  62. Mitsuji, M., Tom, V. D. P., Danny, H., Hisato, K. & Yujiro, H. Involvement of SIP1 in positioning of somite boundaries in the mouse embryo. Dev. Dyn. 234, 332–338 (2005).

    Google Scholar 

  63. van den Berghe, V. et al. Directed migration of cortical interneurons depends on the cell-autonomous action of Sip1. Neuron 77, 70–82 (2013).

    PubMed  Google Scholar 

  64. Arnoux, V., Nassour, M., L’Helgoualc’h, A., Hipskind, R. A. & Savagner, P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol. Biol. Cell 19, 4738–4749 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Terao, M. et al. Enhanced epithelial–mesenchymal transition-like phenotype in N-acetylglucosaminyltransferase V transgenic mouse skin promotes wound healing. J. Biol. Chem. 286, 28303–28311 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Hudson, L. G. et al. Cutaneous wound reepithelialization is compromised in mice lacking functional Slug (Snai2). J. Dermatol. Sci. 56, 19–26 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Gibbons, D. L. & Creighton, C. J. Pan-cancer survey of epithelial–mesenchymal transition markers across the Cancer Genome Atlas. Dev. Dyn. 247, 555–564 (2018).

    CAS  PubMed  Google Scholar 

  68. Tan, T. Z. et al. Epithelial–mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol. Med. 6, 1279–1293 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Lamouille, S., Subramanyam, D., Blelloch, R. & Derynck, R. Regulation of epithelial–mesenchymal and mesenchymal–epithelial transitions by microRNAs. Curr. Opin. Cell Biol. 25, 200–207 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wan Makhtar, W. R. et al. Short stretches of rare codons regulate translation of the transcription factor ZEB2 in cancer cells. Oncogene 36, 6640–6648 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Deshiere, A. et al. Unbalanced expression of CK2 kinase subunits is sufficient to drive epithelial-to-mesenchymal transition by Snail1 induction. Oncogene 32, 1373–1383 (2012).

    PubMed  Google Scholar 

  72. Zhou, B. P. et al. Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition. Nat. Cell Biol. 6, 931–940 (2004).

    CAS  PubMed  Google Scholar 

  73. Viñas-Castells, R. et al. Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability. Nucleic Acids Res. 42, 1079–1094 (2014).

    PubMed  Google Scholar 

  74. Wang, S.-P. et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat. Cell Biol. 11, 694–704 (2009).

    CAS  PubMed  Google Scholar 

  75. Seung-Oe, L., Hongtae, K. & Guhung, J. p53 inhibits tumor cell invasion via the degradation of snail protein in hepatocellular carcinoma. FEBS Lett. 584, 2231–2236 (2010).

    Google Scholar 

  76. Kogan-Sakin, I. et al. Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells. Cell Death Diff. 18, 271–281 (2010).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  78. Zhou, Z. et al. USP51 promotes deubiquitination and stabilization of ZEB1. Am. J. Cancer Res. 7, 2020–2031 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dave, N. et al. Functional cooperation between Snail1 and Twist in the regulation of ZEB1 expression during epithelial to mesenchymal transition. J. Biol. Chem. 286, 12024–12032 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Guaita, S. et al. Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J. Biol. Chem. 277, 39209–39216 (2002).

    CAS  PubMed  Google Scholar 

  81. Tran, D. D., Corsa, C. A. S., Biswas, H., Aft, R. L. & Longmore, G. D. Temporal and spatial cooperation of Snail1 and Twist1 during epithelial–mesenchymal transition predicts for human breast cancer recurrence. Mol. Cancer Res. 9, 1644–1657 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Moreno-Bueno, G. et al. Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition. Cancer Res. 66, 9543–9556 (2006).

    CAS  PubMed  Google Scholar 

  83. Balcik-Ercin, P. et al. Genome-wide analysis of endogenously expressed ZEB2 binding sites reveals inverse correlations between ZEB2 and GalNAc-transferase GALNT3 in human tumors. Cell Oncol. 41, 379–393 (2018).

    CAS  Google Scholar 

  84. Balestrieri, C. et al. Co-optation of tandem DNA repeats for the maintenance of mesenchymal identity. Cell 173, 1150–1164.e14 (2018).

    CAS  PubMed  Google Scholar 

  85. Bildsoe, H. et al. Transcriptional targets of TWIST1 in the cranial mesoderm regulate cell–matrix interactions and mesenchyme maintenance. Dev. Biol. 418, 189–203 (2016).

    CAS  PubMed  Google Scholar 

  86. Diaferia, G. R. et al. Dissection of transcriptional and cis‐regulatory control of differentiation in human pancreatic cancer. EMBO J. 35, 595–617 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Gertz, J. et al. Distinct properties of cell-type-specific and shared transcription factor binding sites. Mol. Cell 52, 25–36 (2016).

    Google Scholar 

  88. Katsura, A. et al. ZEB1‐regulated inflammatory phenotype in breast cancer cells. Mol. Oncol. 11, 1241–1262 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Schmitges, F. W. et al. Multiparameter functional diversity of human C2H2 zinc finger proteins. Genome Res. 26, 1742–1752 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Song, K.-A. et al. Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM. Clin. Cancer Res. 24, 197–208 (2018).

    CAS  PubMed  Google Scholar 

  91. ENCODE Project Consortium. An integrated Encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    Google Scholar 

  92. Tsankov, A. M. et al. Transcription factor binding dynamics during human ES cell differentiation. Nature 518, 344–349 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Yan, J. et al. Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell 154, 801–813 (2013).

    CAS  PubMed  Google Scholar 

  94. Ikeda, K. & Kawakami, K. DNA binding through distinct domains of zinc-finger-homeodomain protein AREB6 has different effects on gene transcription. Eur. J. Biochem. 233, 73–82 (1995).

    CAS  PubMed  Google Scholar 

  95. Remacle, J. E. 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. 18, 5073–5084 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Chang, A. T. et al. An evolutionarily conserved DNA architecture determines target specificity of the TWIST family bHLH transcription factors. Genes Dev. 29, 603–616 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Villarejo, A., Cortés-Cabrera, Á., Molina-Ortíz, P., Portillo, F. & Cano, A. Differential role of Snail1 and Snail2 zinc fingers in E-cadherin repression and epithelial to mesenchymal transition. J. Biol. Chem. 289, 930–941 (2014).

    CAS  PubMed  Google Scholar 

  98. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Montserrat, N. et al. Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma. Hum. Pathol. 43, 632–643 (2012).

    PubMed  Google Scholar 

  100. Morel, A.-P. et al. EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLoS Genet. 8, e1002723 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Blanco, M. J. et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21, 3241–3246 (2002).

    CAS  PubMed  Google Scholar 

  102. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5, 744–749 (2005).

    CAS  PubMed  Google Scholar 

  103. Ye, X. et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525, 256–260 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Visciano, C. et al. Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8–Akt–Slug pathway. Oncogene 34, 5175–5186 (2015).

    CAS  PubMed  Google Scholar 

  105. Beck, B. et al. Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. Cell Stem Cell 16, 67–79 (2015).

    CAS  PubMed  Google Scholar 

  106. Sikandar, S. S. et al. Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. Nat. Commun. 8, 1669 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. Schmidt, J. M. et al. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep. 10, 131–139 (2015).

    CAS  PubMed  Google Scholar 

  108. Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725–736 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhang, P. et al. ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nat. Cell Biol. 16, 864–875 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhang, X. et al. ZEB1 confers chemotherapeutic resistance to breast cancer by activating ATM. Cell Death Dis. 9, 15 (2018).

    PubMed  PubMed Central  Google Scholar 

  111. Morel, A.-P. et al. A stemness-related ZEB1–MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nat. Med. 23, 568–578 (2017).

    CAS  PubMed  Google Scholar 

  112. Sayan, A. E. et al. SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. Proc. Natl Acad. Sci. USA 106, 14884–14889 (2009).

    CAS  PubMed  Google Scholar 

  113. Boohaker, R. J., Cui, X., Stackhouse, M. & Xu, B. ATM-mediated Snail serine 100 phosphorylation regulates cellular radiosensitivity. Radiother. Oncol. 108, 403–408 (2013).

    CAS  PubMed  Google Scholar 

  114. Sun, M. et al. Activation of the ATM–Snail pathway promotes breast cancer metastasis. J. Mol. Cell Biol. 4, 304–315 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Kwok, W. K., Ling, M.-T., Yuen, H. F., Wong, Y.-C. & Wang, X. Role of p14ARF in TWIST-mediated senescence in prostate epithelial cells. Carcinogenesis 28, 2467–2475 (2007).

    CAS  PubMed  Google Scholar 

  116. Vesuna, F., Winnard, P., Raman, V. & Glackin, C. Twist overexpression promotes chromosomal instability in the breast cancer cell line MCF-7. Cancer Genet. Cytogenet. 167, 189–191 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Shih, J.-Y. & Yang, P.-C. The EMT regulator Slug and lung carcinogenesis. Carcinogenesis 32, 1299–1304 (2011).

    CAS  PubMed  Google Scholar 

  118. Wang, J. et al. Snail determines the therapeutic response to mTOR kinase inhibitors by transcriptional repression of 4E-BP1. Nat. Commun. 8, 2207 (2017).

    PubMed  PubMed Central  Google Scholar 

  119. Park, S.-Y. et al. Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells. Oncotarget 6, 37526–37543 (2015).

    PubMed  PubMed Central  Google Scholar 

  120. Jiao, L. et al. Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer. Tumour Biol. 37, 8413–8423 (2016).

    CAS  PubMed  Google Scholar 

  121. Chiu, L. Y. et al. The ERK–ZEB1 pathway mediates epithelial–mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids. Oncogene 36, 242–253 (2017).

    CAS  PubMed  Google Scholar 

  122. Singh, A. et al. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell 15, 489–500 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Alsuliman, A. et al. Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol. Cancer 14, 149 (2015).

    PubMed  PubMed Central  Google Scholar 

  124. Chen, L. et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat. Commun. 5, 5241 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Schönhuber, N. et al. A next-generation dual-recombinase system for time and host specific targeting of pancreatic cancer. Nat. Med. 20, 1340–1347 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. Zhang, T. et al. A genetic cell context-dependent role for ZEB1 in lung cancer. Nat. Commun. 7, 12231 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Wiles, E. T., Bell, R., Thomas, D., Beckerle, M. & Lessnick, S. L. ZEB2 represses the epithelial phenotype and facilitates metastasis in Ewing sarcoma. Genes Cancer 4, 486–500 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Lemma, S. et al. Biological roles and prognostic values of the epithelial–mesenchymal transition-mediating transcription factors Twist, ZEB1 and Slug in diffuse large B-cell lymphoma. Histopathology 62, 326–333 (2013).

    PubMed  Google Scholar 

  129. Behnsawy, H. M., Miyake, H., Harada, K.-I. & Fujisawa, M. Expression patterns of epithelial–mesenchymal transition markers in localized prostate cancer: significance in clinicopathological outcomes following radical prostatectomy. BJU Int. 111, 30–37 (2013).

    PubMed  Google Scholar 

  130. Harada, K.-i, Miyake, H., Kusuda, Y. & Fujisawa, M. Expression of epithelial–mesenchymal transition markers in renal cell carcinoma: impact on prognostic outcomes in patients undergoing radical nephrectomy. BJU Int. 110, E1131–E1137 (2012).

    CAS  PubMed  Google Scholar 

  131. Kihara, A., Wakana, K., Kubota, T. & Kitagawa, M. SLUG expression is an indicator of tumour recurrence in high-grade endometrial carcinomas. Histopathology 69, 374–382 (2016).

    PubMed  Google Scholar 

  132. Colditz, J., Rupf, B., Maiwald, C. & Baniahmad, A. Androgens induce a distinct response of epithelial–mesenchymal transition factors in human prostate cancer cells. Mol. Cell. Biochem. 421, 139–147 (2016).

    CAS  PubMed  Google Scholar 

  133. Kuo, T. C. et al. Angiopoietin-like protein 1 suppresses SLUG to inhibit cancer cell motility. J. Clin. Invest. 123, 1082–1095 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Wang, Y. et al. ASPP2 controls epithelial plasticity and inhibits metastasis through β-catenin-dependent regulation of ZEB1. Nat. Cell Biol. 16, 1092–1104 (2014).

    CAS  PubMed  Google Scholar 

  135. Meng, X. et al. Knockdown of BAG3 induces epithelial–mesenchymal transition in thyroid cancer cells through ZEB1 activation. Cell Death Dis. 5, e1092 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Zhai, D., He, J., Li, X., Gong, L. & Ouyang, Y. Bisphenol A regulates Snail-mediated epithelial–mesenchymal transition in hemangioma cells. Cell Biochem. Funct. 34, 441–448 (2016).

    CAS  PubMed  Google Scholar 

  137. Davis, F. M. et al. Induction of epithelial–mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Oncogene 33, 2307–2316 (2014).

    CAS  PubMed  Google Scholar 

  138. Xu, W. et al. Mutated K-ras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/β-catenin signaling pathway. Cancer Lett. 356, 613–627 (2015).

    CAS  PubMed  Google Scholar 

  139. Ren, T. et al. Discoidin domain receptor 2 (DDR2) promotes breast cancer cell metastasis and the mechanism implicates epithelial–mesenchymal transition programme under hypoxia. J. Pathol. 234, 526–537 (2014).

    CAS  PubMed  Google Scholar 

  140. van den Beucken, T. et al. Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. Nat. Commun. 5, 5203 (2014).

    PubMed  PubMed Central  Google Scholar 

  141. Robichaud, N. et al. Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene 34, 2032–2042 (2015).

    CAS  PubMed  Google Scholar 

  142. Shin, S., Dimitri, C. A., Yoon, S.-O., Dowdle, W. & Blenis, J. ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. Mol. Cell 38, 114–127 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Wu, D. W. et al. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction. Oncogene 36, 5439 (2017).

    CAS  PubMed  Google Scholar 

  144. Terry, S. et al. Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: consequences on susceptibility to cell-mediated cytotoxicity. Oncoimmunology 6, e1271858 (2017).

    PubMed  PubMed Central  Google Scholar 

  145. Liu, Y. et al. HIFs enhance the migratory and neoplastic capacities of hepatocellular carcinoma cells by promoting EMT. Tumour Biol. 35, 8103–8114 (2014).

    CAS  PubMed  Google Scholar 

  146. Yang, S. W. et al. HIF-1α induces the epithelial–mesenchymal transition in gastric cancer stem cells through the Snail pathway. Oncotarget 8, 9535–9545 (2017).

    PubMed  PubMed Central  Google Scholar 

  147. Chen, S. et al. Hypoxia induces TWIST-activated epithelial–mesenchymal transition and proliferation of pancreatic cancer cells in vitro and in nude mice. Cancer Lett. 383, 73–84 (2016).

    CAS  PubMed  Google Scholar 

  148. Joseph, J. V. et al. Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α–ZEB1 axis. Cancer Lett. 359, 107–116 (2015).

    CAS  PubMed  Google Scholar 

  149. Li, H. et al. Insulin-like growth factor-I induces epithelial to mesenchymal transition via GSK-3β and ZEB2 in the BGC-823 gastric cancer cell line. Oncology Lett. 9, 143–148 (2015).

    Google Scholar 

  150. Pantuck, A. J., An, J., Liu, H. & Rettig, M. B. NF-κB-dependent plasticity of the epithelial to mesenchymal transition induced by von Hippel–Lindau inactivation in renal cell carcinomas. Cancer Res. 70, 752–761 (2010).

    CAS  PubMed  Google Scholar 

  151. Sun, Q. et al. Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis. J. Clin. Invest. 128, 531–544 (2018).

    PubMed  Google Scholar 

  152. Xiong, H. et al. Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial–mesenchymal transition. J. Biol. Chem. 287, 5819–5832 (2012).

    CAS  PubMed  Google Scholar 

  153. Yang, C. C. et al. Membrane type 1 matrix metalloproteinase induces an epithelial to mesenchymal transition and cancer stem cell-like properties in SCC9 cells. BMC Cancer 13, 171 (2013).

    PubMed  PubMed Central  Google Scholar 

  154. Cai, W., Ye, Q. & She, Q.-B. Loss of 4E-BP1 function induces EMT and promotes cancer cell migration and invasion via cap-dependent translational activation of snail. Oncotarget 5, 6015–6027 (2014).

    PubMed  PubMed Central  Google Scholar 

  155. Fu, J. et al. p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways. Hepatology 53, 181–192 (2011).

    CAS  PubMed  Google Scholar 

  156. Kamiya, T., Goto, A., Kurokawa, E., Hara, H. & Adachi, T. Cross talk mechanism among EMT, ROS, and histone acetylation in phorbol ester-treated human breast cancer MCF-7 cells. Oxid. Med. Cell. Longev. 2016, 1284372 (2016).

    PubMed  PubMed Central  Google Scholar 

  157. Peiqi, L. et al. Expression of SRSF3 is correlated with carcinogenesis and progression of oral squamous cell carcinoma. Int. J. Med. Sci. 13, 533–539 (2016).

    PubMed  PubMed Central  Google Scholar 

  158. An, J. et al. Hyperactivated JNK is a therapeutic target in pVHL-deficient renal cell carcinoma. Cancer Res. 73, 1374–1385 (2013).

    CAS  PubMed  Google Scholar 

  159. Ahn, Y.-H. et al. ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression. J. Clin. Invest. 122, 3170–3183 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Low-Marchelli, J. M. et al. Twist1 induces CCL2 and recruits macrophages to promote angiogenesis. Cancer Res. 73, 662–671 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Rönsch, K. et al. SNAIL1 combines competitive displacement of ASCL2 and epigenetic mechanisms to rapidly silence the EPHB3 tumor suppressor in colorectal cancer. Mol. Oncol. 9, 335–354 (2015).

    PubMed  Google Scholar 

  162. Cieply, B., Farris, J., Denvir, J., Ford, H. L. & Frisch, S. M. Epithelial–mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2. Cancer Res. 73, 6299–6309 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Pfeifer, M. et al. L1CAM expression in endometrial carcinomas is regulated by usage of two different promoter regions. BMC Mol. Biol. 11, 64 (2010).

    PubMed  PubMed Central  Google Scholar 

  164. Huang, C.-H. et al. Regulation of membrane-type 4 matrix metalloproteinase by SLUG contributes to hypoxia-mediated metastasis. Neoplasia 11, 1371–1382 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Natsuizaka, M. et al. Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat. Commun. 8, 1758 (2017).

    PubMed  PubMed Central  Google Scholar 

  166. Eckert, M. A. et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell 19, 372–386 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Escrivà, M. et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol. Cell. Biol. 28, 1528–1540 (2008).

    PubMed  PubMed Central  Google Scholar 

  168. Liu, Y. et al. Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis. Nat. Commun. 5, 5660 (2014).

    PubMed  Google Scholar 

  169. Kinugasa, H. et al. Mitochondrial SOD2 regulates epithelial–mesenchymal transition and cell populations defined by differential CD44 expression. Oncogene 34, 5229–5239 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Larriba, M. J. et al. Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis 30, 1459–1468 (2009).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to our colleagues for all of the publications that could not be referenced owing to space limitations. This work was supported by grants from the DFG (DFG BR 1399/9-1, DFG BR1399/10-1 and DFG BR4145/1-1) and the IZKF (project F4-46) of the FAU Erlangen-Nürnberg.

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  1. Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Erlangen, Germany

    Marc P. Stemmler, Rebecca L. Eccles, Simone Brabletz & Thomas Brabletz

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Stemmler, M.P., Eccles, R.L., Brabletz, S. et al. Non-redundant functions of EMT transcription factors. Nat Cell Biol 21, 102–112 (2019). https://doi.org/10.1038/s41556-018-0196-y

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