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.

  • Letter
  • Published:

Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis

Nature Cell Biology volume 8, pages 631–639 (2006)Cite this article

An Author Correction to this article was published on 16 June 2021

This article has been updated

Abstract

Defining the functional modules within transcriptional regulatory factors that govern switching between repression and activation events is a central issue in biology. Recently, we have reported the dynamic role of a β-catenin–reptin chromatin remodelling complex in regulating a metastasis suppressor gene KAI1 (ref.1), which is capable of inhibiting the progression of tumour metastasis2,3,4,5. Here, we identify signalling factors that confer repressive function on reptin and hence repress the expression of KAI1. Biochemical purification of a reptin-containing complex has revealed the presence of specific desumoylating enzymes that reverse the sumoylation of reptin that underlies its function as a repressor. Desumoylation of reptin alters the repressive function of reptin and its association with HDAC1. Furthermore, the sumoylation status of reptin modulates the invasive activity of cancer cells with metastatic potential. These data clearly define a functional model and provide a novel link for SUMO modification in cancer metastasis.

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: Desumoylating enzymes are components of a reptin-containing complex.
Figure 2: Lys 456 of reptin is critical for SUMO modification.
Figure 3: Desumoylation of reptin by SENP1 both in vitro and in vivo.
Figure 4: Sumoylation status of reptin affects the metastatic potential of KAI1.
Figure 5: SENP1 and Ubc9 modulate the invasive activity of LNCaP and RWPE1 cells.

Similar content being viewed by others

Change history

References

  1. Kim, J. H. et al. Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes. Nature 434, 921–926 (2005).

    Article  CAS  Google Scholar 

  2. Shevde, L. A. & Welch, D. R. Metastasis suppressor pathways — an evolving paradigm. Cancer Lett. 198, 1–20 (2003).

    Article  CAS  Google Scholar 

  3. Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cell. Nature Rev. Cancer 3, 55–63 (2002).

    Article  Google Scholar 

  4. Petrylak, D. P. Metastases suppressors and prostate cancer. Nature Med. 1, 739–740 (1995).

    Article  CAS  Google Scholar 

  5. Dong, J. -T. et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268, 884–886 (1995).

    Article  CAS  Google Scholar 

  6. Glass, C. K. & Rosenfeld, M. G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000).

    CAS  PubMed  Google Scholar 

  7. McKenna, N. J. & O'Malley, B. W. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108, 465–474 (2002).

    Article  CAS  Google Scholar 

  8. Baek, S. H. & Rosenfeld, M. G. Nuclear receptor coregulators: their modification codes and regulatory mechanism by translocation. Biochem. Biophys. Res. Commun. 319, 707–714 (2004).

    Article  CAS  Google Scholar 

  9. Bauer, A. et al. Pontin52 and Reptin52 function as antagonistic regulators of β-catenin signaling activity. EMBO J. 19, 6121–6130 (2000).

    Article  CAS  Google Scholar 

  10. Feng, Y., Lee, N. & Fearon, E. R. TIP49 regulates β-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling. Cancer Res. 63, 8726–8734 (2003).

    CAS  PubMed  Google Scholar 

  11. Kanemaki, M. et al. TIP49b, a new RuvB-like DNA helicase, is included in a complex together with another RuvB-like DNA helicase, TIP49a. J. Biol. Chem. 274, 22437–22444 (1999).

    Article  CAS  Google Scholar 

  12. Jonsson, Z. O., Jha, S., Wohlschlegel J. A. & Dutta, A. Rvb1p/Rvb2p recruit Arp5p and assemble a functional Ino80 chromatin remodeling complex. Mol. Cell 16, 465–477 (2004).

    Article  CAS  Google Scholar 

  13. Francis, N. J., Saurin, A. J., Shao, Z. & Kingston, R. E. Reconstitution of a functional core polycomb repressive complex. Mol. Cell 8, 545–556 (2001).

    Article  CAS  Google Scholar 

  14. Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).

    Article  CAS  Google Scholar 

  15. Fuchs, M. et al. The p400 complex is an essential E1A transformation target. Cell 106, 297–307 (2001).

    Article  CAS  Google Scholar 

  16. Billin, A. N., Thirlwell, H. & Ayer, D. E. β-catenin-histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator. Mol. Cell Biol. 20, 6882–6690 (2000).

    Article  CAS  Google Scholar 

  17. Baek, S. H. et al. Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway. Proc. Natl. Acad. Sci. USA 100, 3245–3250 (2003).

    Article  CAS  Google Scholar 

  18. Seeler, J. S. et al. Common properties of nuclear body protein SP100 and TIF1α chromatin factor: role of SUMO modification. Mol. Cell Biol. 21, 3314–3324 (2001).

    Article  CAS  Google Scholar 

  19. Tatham, M. H. et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J. Biol. Chem. 276, 35368–35374 (2001).

    Article  CAS  Google Scholar 

  20. Johnson, E. S. Protein modification by SUMO. Annu. Rev. Biochem. 73, 355–382 (2004).

    Article  CAS  Google Scholar 

  21. Li, S. J. & Hochstrasser, M. A new protease required for cell-cycle progression in yeast. Nature 398, 246–351 (1999).

    Article  CAS  Google Scholar 

  22. Kim, K. I. et al. A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J. Biol. Chem. 275, 14102–14106 (2000).

    Article  CAS  Google Scholar 

  23. Best, J. L. et al. SUMO-1 protease-1 regulates gene transcription through PML. Mol. Cell 10, 843–855 (2002).

    Article  CAS  Google Scholar 

  24. Bachant, J., Alcasabas, A., Blat, Y., Kleckner, N. & Elledge, S. J. The SUMO-1 isopeptidase Smt4 is linked to centromeric cohesion through SUMO-1 modification of DNA topoisomerase II. Mol. Cell 9, 1169–1182 (2002).

    Article  CAS  Google Scholar 

  25. Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).

    Article  CAS  Google Scholar 

  26. Huang, T. T., Wuerzberger-Davis, S. M., Wu, Z. H. & Miyamoto, S. Sequential modification of NEMO/IKKγ by SUMO-1 and ubiquitin mediates NF-κB activation by genotoxic stress. Cell 115, 565–576 (2003).

    Article  CAS  Google Scholar 

  27. Ross, S., Best, J. L., Zon, L. I. & Gill, G. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol. Cell 10, 831–842 (2002).

    Article  CAS  Google Scholar 

  28. Salghetti, S. E., Caudy, A. A., Chenoweth, J. G. & Tansey, W. P. Regulation of transcriptional activation domain function by ubiquitin. Science 293, 1651–1653 (2001).

    Article  CAS  Google Scholar 

  29. Alarcon-Vargas, D. & Ronai, Z. SUMO in cancer-wrestlers wanted. Cancer Biol. Therapy 1, 237–242 (2002).

    Article  CAS  Google Scholar 

  30. Zheng, G. & Yang, Y. C. ZNF76, a novel transcriptional repressor targeting TATA-binding protein, is modulated by sumoylation. J. Biol. Chem. 279, 42410–42421 (2004).

    Article  CAS  Google Scholar 

  31. Girdwood, D. et al. p300 transcriptional repression is mediated by SUMO modification. Mol. Cell 11, 1043–1054 (2003).

    Article  CAS  Google Scholar 

  32. Baek, S. H. et al. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-κB and β-amyloid precursor protein. Cell 110, 55–67 (2002).

    Article  CAS  Google Scholar 

  33. Cheng, J. et al. SENP1 enhances androgen receptor-dependent transcription through desumoylation of histone deacetylase 1. Mol. Cell Biol. 24, 6021–6028 (2004).

    Article  CAS  Google Scholar 

  34. Kurihara, I. et al. Ubc9 and protein inhibitor of activated STAT1 activate chicken ovalbumin upstream promoter-transcription factor I-mediated human CYP11B2 gene transcription. J. Biol. Chem. 280, 6721–6730 (2005).

    Article  CAS  Google Scholar 

  35. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in mammalian cell culture. Nature 411, 494–498 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. G. Rosenfeld (Howard Hughes Medical Institute), C. K. Glass (University of California at San Diego), C. Y. Choi (Sung Kyun Kwan University) and E. Park (Seoul National University) for critical reading of our manuscript. This work was supported by Korea Research Foundation Grant (MOEHRD, Basic Research Promotion Fund), the National Research and Development programme for cancer control from the Ministry of Health & Welfare, and Science Research Center (SRC) programme of the Ministry of Science and Technology (MOST) and the Koreas Science and Engineering Foundation (KOSEF), Brain Koreas 21 (BK21) and Seoul Science Fellowship (H.J.C and B.K), and Ubiquitome Research Program from MOST/KOSEF (C.H.C and K.I.K.).

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul, 151–742, South Korea

    Jung Hwa Kim, Hee June Choi, Bogyou Kim, Ji Min Lee, Ik Soo Kim, Moon Hee Lee, Soo Joon Choi, Chin Ha Chung & Sung Hee Baek

  2. School of Agricultural Biotechnology, Seoul National University, Seoul, 151–742, South Korea

    Mi Hyang Kim & Su-Il Kim

  3. Department of Biological Sciences, Sookmyung Women's University, Seoul, 140-742, South Korea

    Keun Il Kim

Authors
  1. Jung Hwa Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hee June Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bogyou Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mi Hyang Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ji Min Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ik Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Moon Hee Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Soo Joon Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Keun Il Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Su-Il Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chin Ha Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sung Hee Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sung Hee Baek.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3 and S4 (PDF 86 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J., Choi, H., Kim, B. et al. Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis. Nat Cell Biol 8, 631–639 (2006). https://doi.org/10.1038/ncb1415

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1415

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing