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The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity

Abstract

Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of transcription factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell–cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo, and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro. In human colorectal cancer, ZEB1 expression was limited to the tumour–host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.

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References

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

    CAS  Article  PubMed  Google Scholar 

  • Bilder D . (2004). Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev 18: 1909–1925.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  • Brumby AM, Richardson HE . (2005). Using Drosophila melanogaster to map human cancer pathways. Nat Rev Cancer 5: 626–639.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  • Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H . (2006). NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26: 711–724.

    Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  • Condeelis J, Pollard JW . (2006). Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124: 263–266.

    CAS  Article  PubMed  Google Scholar 

  • De Craene B, Gilbert B, Stove C, Bruyneel E, van Roy F, Berx G . (2005a). The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res 65: 6237–6244.

    CAS  Article  PubMed  Google Scholar 

  • De Craene B, van Roy F, Berx G . (2005b). Unraveling signalling cascades for the Snail family of transcription factors. Cell Signal 17: 535–547.

    CAS  Article  PubMed  Google Scholar 

  • Dohadwala M, Yang SC, Luo J, Sharma S, Batra RK, Huang M et al. (2006). Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res 66: 5338–5345.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  • Eger A, Mikulits W . (2005). Models of epithelial-mesenchymal transition. Drug Discovery Today: Disease Models 2: 57–63.

    CAS  Google Scholar 

  • Eger A, Stockinger A, Schaffhauser B, Beug H, Foisner R . (2000). Epithelial mesenchymal transition by c-Fos estrogen receptor activation involves nuclear translocation of beta-catenin and upregulation of beta-catenin/lymphoid enhancer binding factor-1 transcriptional activity. J Cell Biol 148: 173–188.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Grooteclaes ML, Frisch SM . (2000). Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 19: 3823–3828.

    CAS  Article  PubMed  Google Scholar 

  • Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E et al. (2002). Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem 277: 39209–39216.

    CAS  Article  PubMed  Google Scholar 

  • Gupta PB, Kuperwasser C, Brunet JP, Ramaswamy S, Kuo WL, Gray JW et al. (2005). The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nat Genet 37: 1047–1054.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Huber MA, Kraut N, Beug H . (2005). Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17: 548–558.

    CAS  Article  PubMed  Google Scholar 

  • Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH et al. (2006). 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 66: 2725–2731.

    CAS  Article  PubMed  Google Scholar 

  • Lacroix M, Leclercq G . (2004). Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat 83: 249–289.

    CAS  Article  PubMed  Google Scholar 

  • Michel D, Arsanto JP, Massey-Harroche D, Beclin C, Wijnholds J, Le Bivic A . (2005). PATJ connects and stabilizes apical and lateral components of tight junctions in human intestinal cells. J Cell Sci 118: 4049–4057.

    CAS  Article  PubMed  Google Scholar 

  • Moreno-Bueno G, Cubillo E, Sarrio D, Peinado H, Rodriguez-Pinilla SM, Villa S et al. (2006). 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.

    CAS  Article  PubMed  Google Scholar 

  • Nishimura G, Manabe I, Tsushima K, Fujiu K, Oishi Y, Imai Y et al. (2006). DeltaEF1 mediates TGF-beta signaling in vascular smooth muscle cell differentiation. Dev Cell 11: 93–104.

    CAS  Article  PubMed  Google Scholar 

  • Ohira T, Gemmill RM, Ferguson K, Kusy S, Roche J, Brambilla E et al. (2003). WNT7a induces E-cadherin in lung cancer cells. Proc Natl Acad Sci USA 100: 10429–10434.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Pacher M, Seewald MJ, Mikula M, Oehler S, Mogg M, Vinatzer U et al. (2006). Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells. Carcinogenesis 28: 49–59.

    Article  PubMed  Google Scholar 

  • Palmer HG, Larriba MJ, Garcia JM, Ordonez-Moran P, Pena C, Peiro S et al. (2004). The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat Med 10: 917–919.

    CAS  Article  PubMed  Google Scholar 

  • Peinado H, Portillo F, Cano A . (2004). Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol 48: 365–375.

    CAS  Article  PubMed  Google Scholar 

  • Pena C, Garcia JM, Garcia V, Silva J, Dominguez G, Rodriguez R et al. (2006). The expression levels of the transcriptional regulators p300 and CtBP modulate the correlations between SNAIL, ZEB1, E-cadherin and vitamin D receptor in human colon carcinomas. Int J Cancer 119: 2098–2104.

    CAS  Article  PubMed  Google Scholar 

  • Pena C, Garcia JM, Silva J, Garcia V, Rodriguez R, Alonso I et al. (2005). E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. Hum Mol Genet 14: 3361–3370.

    CAS  Article  PubMed  Google Scholar 

  • Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA et al. (2001). A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem 276: 27424–27431.

    CAS  Article  PubMed  Google Scholar 

  • Shin K, Straight S, Margolis B . (2005). PATJ regulates tight junction formation and polarity in mammalian epithelial cells. J Cell Biol 168: 705–711.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  • Thiery JP . (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

    CAS  Article  PubMed  Google Scholar 

  • Thiery JP, Sleeman JP . (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7: 131–142.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Wheelock MJ, Johnson KR . (2003). Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol 19: 207–235.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank Gabriele Stengl and Peter Steinlein, Institute of Molecular Pathology, Vienna, for Flow Cytometry (FACS) experiments. Furthermore, we thank Jürgen Pollheimer and Martin Knofler for their technical expertise in transpore migration assays and Heidemarie Huber for support in immunohistochemistry. This study was supported by funds from the Hochschuljubiläumsstiftung of the city of Vienna to AE (H-703/2005), by grants from the Austrian Science Research Fund (FWF) No. SFB 006 to RF (603) and HB (612), SFB-F28 to WM and by funds of the Austrian Ministry of Education, Science, and the Arts (Austrian Genome Research Program GEN-AU) to MS, WS, NS, AW. AS is supported by the ÖAD-Pakistan Scholarship programme.

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Correspondence to R Foisner or A Eger.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Aigner, K., Dampier, B., Descovich, L. et al. The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26, 6979–6988 (2007). https://doi.org/10.1038/sj.onc.1210508

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Keywords

  • epithelial to mesenchymal transition
  • invasion
  • transcription
  • epithelial polarity
  • cell adhesion

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