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TGF-β1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells

Abstract

In spite of a large number of transforming growth factor β1 (TGF-β1)-regulated genes, the nature of its targets with roles in transformation continues to be poorly understood. Here, we discovered that TGF-β1 stimulates transcription of metastasis-associated protein 1 (MTA1), a dual master coregulator, in epithelial cells, and that MTA1 status is a determinant of TGF-β1-induced epithelial-to-mesenchymal transition (EMT) phenotypes. In addition, we found that MTA1/polymerase II/activator protein-1 (AP-1) co-activator complex interacts with the FosB-gene chromatin and stimulates its transcription, and FosB in turn, utilizes FosB/histone deacetylase 2 complex to repress E-cadherin expression in TGF-β1-stimulated mammary epithelial cells. These findings suggest that TGF-β1 regulates the components of EMT via stimulating the expression of MTA1, which in turn, induces FosB to repress E-cadherin expression and thus, revealed an inherent function of MTA1 as a target and effector of TGF-β1 signaling in epithelial cells.

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References

  • Balasenthil S, Gururaj AE, Talukder AH, Bagheri-Yarmand R, Arrington T, Haas BJ et al. (2007). Identification of Pax5 as a target of MTA1 in B-cell lymphomas. Cancer Res 67: 7132–7138.

    Article  CAS  Google Scholar 

  • Bui-Nguyen TM, Pakala SB, Sirigiri RD, Xia W, Hung MC, Sarin SK et al. (2010). NF-kappaB signaling mediates the induction of MTA1 by hepatitis B virus transactivator protein HBx. Oncogene 29: 1179–1189.

    Article  CAS  Google Scholar 

  • Condeelis J, Segall JE . (2003). Intravital imaging of cell movement in tumours. Nat Rev Cancer 3: 921–930.

    Article  CAS  Google Scholar 

  • Dannenmann C, Shabani N, Friese K, Jeschke U, Mylonas I, Bruning A . (2008). The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ERbeta, and enhances expression of oncogenic cytokine GRO. Cancer Biol Ther 7: 1460–1467.

    Article  CAS  Google Scholar 

  • Deckers M, van Dinther M, Buijs J, Que I, Lowik C, van der Pluijm G et al. (2006). The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res 66: 2202–2209.

    Article  CAS  Google Scholar 

  • Eferl R, Wagner EF . (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3: 859–868.

    Article  CAS  Google Scholar 

  • Gery S, Tanosaki S, Bose S, Bose N, Vadgama J, Koeffler HP . (2005). Down-regulation and growth inhibitory role of C/EBPalpha in breast cancer. Clin Cancer Res 11: 3184–3190.

    Article  CAS  Google Scholar 

  • Gururaj AE, Singh RR, Rayala SK, Holm C, den Hollander P, Zhang H et al. (2006). MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc Natl Acad Sci USA 103: 6670–6675.

    Article  CAS  Google Scholar 

  • Hofer MD, Menke A, Genze F, Gierschik P, Giehl K . (2004). Expression of MTA1 promotes motility and invasiveness of PANC-1 pancreatic carcinoma cells. Br J Cancer 90: 455–462.

    Article  CAS  Google Scholar 

  • Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED et al. (2007). Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression. J Cell Physiol 213: 374–383.

    Article  CAS  Google Scholar 

  • Kumar R, Wang RA, Mazumdar A, Talukder AH, Mandal M, Yang Z et al. (2002). A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm. Nature 418: 654–657.

    Article  CAS  Google Scholar 

  • Kurisaki K, Kurisaki A, Valcourt U, Terentiev AA, Pardali K, Ten Dijke P et al. (2003). Nuclear factor YY1 inhibits transforming growth factor beta- and bone morphogenetic protein-induced cell differentiation. Mol Cell Biol 23: 4494–4510.

    Article  CAS  Google Scholar 

  • Lee TC, Zhang Y, Schwartz RJ . (1994). Bifunctional transcriptional properties of YY1 in regulating muscle actin and c-myc gene expression during myogenesis. Oncogene 9: 1047–1052.

    CAS  PubMed  Google Scholar 

  • MacLellan WR, Lee TC, Schwartz RJ, Schneider MD . (1994). Transforming growth factor-beta response elements of the skeletal alpha-actin gene. combinatorial action of serum response factor, YY1, and the SV40 enhancer-binding protein, TEF-1. J Biol Chem 269: 16754–16760.

    CAS  PubMed  Google Scholar 

  • Mahoney MG, Simpson A, Jost M, Noe M, Kari C, Pepe D et al. (2002). Metastasis-associated protein (MTA)1 enhances migration, invasion, and anchorage-independent survival of immortalized human keratinocytes. Oncogene 21: 2161–2170.

    Article  CAS  Google Scholar 

  • Manavathi B, Kumar R . (2007). Metastasis tumor antigens, an emerging family of multifaceted master coregulators. J Biol Chem 282: 1529–1533.

    Article  CAS  Google Scholar 

  • Massague J, Seoane J, Wotton D . (2005). Smad transcription factors. Genes Dev 19: 2783–2810.

    Article  CAS  Google Scholar 

  • Mazumdar A, Wang RA, Mishra SK, Adam L, Bagheri-Yarmand R, Mandal M et al. (2001). Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol 3: 30–37.

    Article  CAS  Google Scholar 

  • Michl P, Downward J . (2006). CUTL1: a key mediator of TGFbeta-induced tumor invasion. Cell Cycle 5: 132–134.

    Article  CAS  Google Scholar 

  • Michl P, Ramjaun AR, Pardo OE, Warne PH, Wagner M, Poulsom R et al. (2005). CUTL1 is a target of TGF(beta) signaling that enhances cancer cell motility and invasiveness. Cancer Cell 7: 521–532.

    Article  CAS  Google Scholar 

  • Molli PR, Singh RR, Lee SW, Kumar R . (2008). MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene. Oncogene 27: 1971–1980.

    Article  CAS  Google Scholar 

  • Ohnishi YN, Sakumi K, Yamazaki K, Ohnishi YH, Miura T, Tominaga Y et al. (2008). Antagonistic regulation of cell-matrix adhesion by FosB and DeltaFosB/Delta2DeltaFosB encoded by alternatively spliced forms of fosB transcripts. Mol Biol Cel 19: 4717–4729.

    Article  CAS  Google Scholar 

  • Pakala SB, Bui-Nguyen TM, Reddy SD, Li DQ, Peng S, Rayala SK et al. (2010). Regulation of NF-kappaB circuitry by a component of the nucleosome remodeling and deacetylase complex controls inflammatory response homeostasis. J Biol Chem 285: 23590–23597.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Radisky DC . (2005). Epithelial-mesenchymal transition. J Cell Sci 118: 4325–4326.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Tong D, Heinze G, Schremmer M, Schuster E, Czerwenka K, Leodolter S et al. (2007). Expression of the human MTA1 gene in breast cell lines and in breast cancer tissues. Oncol Res 16: 465–470.

    Article  CAS  Google Scholar 

  • von Burstin J, Eser S, Paul MC, Seidler B, Brandl M, Messer M et al. (2009). E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology 137: 361–371.

    Article  CAS  Google Scholar 

  • Zavadil J, Bottinger EP . (2005). TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24: 5764–5774.

    Article  CAS  Google Scholar 

  • Zhang H, Stephens LC, Kumar R . (2006). Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer. Clin Cancer Res 12: 1479–1486.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Dr Toshio Matsumoto for FosB-promoter constructs and Dr Eric R. Fearon for E-cadherin promoter construct. The work was supported by NIH Grant CA98823 (RK).

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Correspondence to R Kumar.

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Pakala, S., Singh, K., Reddy, S. et al. TGF-β1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells. Oncogene 30, 2230–2241 (2011). https://doi.org/10.1038/onc.2010.608

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