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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
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.
Condeelis J, Segall JE . (2003). Intravital imaging of cell movement in tumours. Nat Rev Cancer 3: 921–930.
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.
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.
Eferl R, Wagner EF . (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3: 859–868.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Manavathi B, Kumar R . (2007). Metastasis tumor antigens, an emerging family of multifaceted master coregulators. J Biol Chem 282: 1529–1533.
Massague J, Seoane J, Wotton D . (2005). Smad transcription factors. Genes Dev 19: 2783–2810.
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.
Michl P, Downward J . (2006). CUTL1: a key mediator of TGFbeta-induced tumor invasion. Cell Cycle 5: 132–134.
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.
Molli PR, Singh RR, Lee SW, Kumar R . (2008). MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene. Oncogene 27: 1971–1980.
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.
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.
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.
Radisky DC . (2005). Epithelial-mesenchymal transition. J Cell Sci 118: 4325–4326.
Thiery JP . (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.
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.
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.
Zavadil J, Bottinger EP . (2005). TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24: 5764–5774.
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.
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).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.608