Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Poly(ADP-ribose)-dependent regulation of Snail1 protein stability

Oncogene volume 30, pages 4365–4372 (2011)Cite this article

Subjects

Abstract

Snail1 is a master regulator of the epithelial–mesenchymal transition (EMT) and has been implicated in key tumor biological processes such as invasion and metastasis. It has been previously shown that poly(ADP-ribose) polymerase-1 (PARP-1) knockdown, but not PARP inhibition, downregulates the expression of Snail1. In this study we have characterized a novel regulatory mechanism controlling Snail1 protein expression through poly(ADP-ribosyl)ation. The effect is not only limited to repression of Snail1 transcription but also to downregulated Snail1 protein stability. PARP-1 (but not PARP-2) poly(ADP) ribosylates Snail1, both in vivo and in vitro, and interacts with Snail1, an association that is sensitive to PARP inhibitors. PARP inhibition has also clear effects on EMT phenotype of different tumor cells, including Snail1 downregulation, E-cadherin upregulation, decreased cell elongation and invasiveness. Therefore, this study reveals a new regulatory mechanism of Snail1 activation through poly(ADP-ribosyl)ation with consequences in malignant transformation through EMT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Aguilar-Quesada R, Munoz-Gamez JA, Martin-Oliva D, Peralta-Leal A, Quiles-Perez R, Rodriguez-Vargas JM et al. (2007). Modulation of transcription by PARP-1: consequences in carcinogenesis and inflammation. Curr Med Chem 14: 1179–1187.

    Article  CAS  Google Scholar 

  • Ame JC, Rolli V, Schreiber V, Niedergang C, Apiou F, Decker P et al. (1999). PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem 274: 17860–17868.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Barbera MJ, Puig I, Dominguez D, Julien-Grille S, Guaita-Esteruelas S, Peiro S et al. (2004). Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 23: 7345–7354.

    Article  CAS  Google Scholar 

  • Barrallo-Gimeno A, Nieto MA . (2005). The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132: 3151–3161.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A . (2003). The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 116: 499–511.

    Article  CAS  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.

    Article  CAS  Google Scholar 

  • Cavallaro U, Christofori G . (2004). Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4: 118–132.

    Article  CAS  Google Scholar 

  • Dantzer F, Giraud-Panis MJ, Jaco I, Ame JC, Schultz I, Blasco M et al. (2004). Functional interaction between poly(ADP-Ribose) polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates TRF2. Mol Cell Biol 24: 1595–1607.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB et al. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434: 917–921.

    Article  CAS  Google Scholar 

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

    Article  CAS  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.

    Article  CAS  Google Scholar 

  • Guarino M . (1995). Epithelial-to-mesenchymal change of differentiation. From embryogenetic mechanism to pathological patterns. Histol Histopathol 10: 171–184.

    CAS  PubMed  Google Scholar 

  • Guarino M . (2007). Epithelial-mesenchymal transition and tumour invasion. Int J Biochem Cell Biol 39: 2153–2160.

    Article  CAS  Google Scholar 

  • Hassa PO, Hottiger MO . (2008). The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci 13: 3046–3082.

    Article  CAS  Google Scholar 

  • Ikushima H, Miyazono K . (2010). TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 10: 415–424.

    Article  CAS  Google Scholar 

  • Jagtap P, Szabo C . (2005). Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4: 421–440.

    Article  CAS  Google Scholar 

  • Kim MY, Zhang T, Kraus WL . (2005). Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal. Genes Dev 19: 1951–1967.

    Article  CAS  Google Scholar 

  • Lasfar A, Cohen-Solal KA . (2010). Resistance to transforming growth factor beta-mediated tumor suppression in melanoma: are multiple mechanisms in place? Carcinogenesis 31: 1710–1717.

    Article  CAS  Google Scholar 

  • Lin W, Ame JC, Aboul-Ela N, Jacobson EL, Jacobson MK . (1997). Isolation and characterization of the cDNA encoding bovine poly(ADP-ribose) glycohydrolase. J Biol Chem 272: 11895–11901.

    Article  CAS  Google Scholar 

  • Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G . (1998). XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol 18: 3563–3571.

    Article  CAS  Google Scholar 

  • McPhee TR, McDonald PC, Oloumi A, Dedhar S . (2008). Integrin-linked kinase regulates E-cadherin expression through PARP-1. Dev Dyn 237: 2737–2747.

    Article  CAS  Google Scholar 

  • Nieto MA . (2002). The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3: 155–166.

    Article  CAS  Google Scholar 

  • Pardali K, Moustakas A . (2007). Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775: 21–62.

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Peinado H, Portillo F, Cano A . (2005). Switching on-off Snail: LOXL2 versus GSK3beta. Cell Cycle 4: 1749–1752.

    Article  CAS  Google Scholar 

  • Sarrio D, Perez-Mies B, Hardisson D, Moreno-Bueno G, Suarez A, Cano A et al. (2004). Cytoplasmic localization of p120ctn and E-cadherin loss characterize lobular breast carcinoma from preinvasive to metastatic lesions. Oncogene 23: 3272–3283.

    Article  CAS  Google Scholar 

  • Schreiber V, Dantzer F, Ame JC, de Murcia G . (2006). Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7: 517–528.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Virag L, Szabo C . (2002). The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54: 375–429.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge Laura López for her technical assistance. MIR is recipient of a postdoctoral fellowship financed by the program JAE-Doc of CSIC. She was also funded by Junta de Andalucía Short-Term Fellowships to stay at the Département ‘Intégrité du Génome’ de I'UMR 7175, École Supérieure de Biotechnologie de Strasbourg, Strasbourg, France and Ministerio de Ciencia ‘Programa José Castillejo’ to stay at the Department of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands. This work was supported by Ministerio de Ciencia e Innovación SAF2006-01094; SAF2009-13281-C02-01, Fundación La Caixa BM06-219-0; and Junta de Andalucía P07-CTS-0239 to FJO; Ministerio de Educación y Ciencia SAF2007-64597 and ‘Ministerio de Ciencia y Tecnología’ (SAF2006-03399) and ‘la Fundación Científica de la Asociación Española contra el Cáncer’ to AGH.

Author information

Authors and Affiliations

  1. Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain

    M I Rodríguez, A González-Flores & F J Oliver

  2. Département ‘Intégrité du Génome’ de l'UMR 7175, École Supérieure de Biotechnologie de Strasbourg, Strasbourg, France

    F Dantzer

  3. The Netherlands Cancer Institute, Amsterdam, The Netherlands

    J Collard

  4. Programa de Recerca en Càncer, IMIM-Hospital del Mar, Barcelona, Spain

    A G de Herreros

Authors
  1. M I Rodríguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A González-Flores
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Dantzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Collard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A G de Herreros
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F J Oliver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F J Oliver.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodríguez, M., González-Flores, A., Dantzer, F. et al. Poly(ADP-ribose)-dependent regulation of Snail1 protein stability. Oncogene 30, 4365–4372 (2011). https://doi.org/10.1038/onc.2011.153

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.153

Keywords

This article is cited by

Search

Advanced search

Quick links