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:

Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes

Nature volume 434, pages 921–926 (2005)Cite this article

An Author Correction to this article was published on 05 July 2022

This article has been updated

Abstract

Defining the molecular strategies that integrate diverse signalling pathways in the expression of specific gene programmes that are critical in homeostasis and disease remains a central issue in biology. This is particularly pertinent in cancer biology because downregulation of tumour metastasis suppressor genes is a common occurrence1,2, and the underlying molecular mechanisms are not well established. Here we report that the downregulation of a metastasis suppressor gene, KAI1, in prostate cancer cells involves the inhibitory actions of β-catenin, along with a reptin chromatin remodelling complex. This inhibitory function of β-catenin–reptin requires both increased β-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of β-catenin–reptin components that mediate the repressive state serve to antagonize a Tip60 coactivator complex3,4,5,6,7,8 that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of β-catenin–reptin and the Tip60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-κB target genes.

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: KAI1 is a functional metastasis suppressor gene.
Figure 2: Failure of Tip60 recruitment on KAI1 promoter is crucial for downregulation of KAI1.
Figure 3: β-Catenin downregulates a subset of NF-κB target genes along with reptin.
Figure 4: Tip60 and β-catenin switch affects the metastatic potential.

Similar content being viewed by others

Change history

References

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

    Article  CAS  Google Scholar 

  2. Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cell. Nature Rev. Cancer3, 55–63 (2002)

    Article  Google Scholar 

  3. 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 

  4. Bauer, A., Huber, O. & Kemler, R. Pontin52, an interaction partner of β-catenin binds to the TATA box binding protein. Proc. Natl Acad. Sci. USA95, 14787–14792 (1998)

    Article  ADS  CAS  Google Scholar 

  5. 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 

  6. Wood, M. A., McMahon, S. B. & Cole, M. D. An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-Myc. Mol. Cell5, 321–330 (2000)

    Article  CAS  Google Scholar 

  7. Rottbauer, W. et al. Reptin and pontin antagonistically regulate heart growth in zebrafish embryos. Cell111, 661–672 (2002)

    Article  CAS  Google Scholar 

  8. Ikura, T. et al. Involvement of the Tip60 histone acetylase complex in DNA repair and apoptosis. Cell102, 463–473 (2000)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Dong, J.-T. et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science268, 884–886 (1995)

    Article  ADS  CAS  Google Scholar 

  11. Dong, J.-T. et al. Down-regulation of the KAI1 metastasis suppressor gene during the progression of human prostatic cancer infrequently involves gene mutation or allelic loss. Cancer Res.56, 4387–4390 (1996)

    CAS  PubMed  Google Scholar 

  12. 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. Cell110, 55–67 (2002)

    Article  CAS  Google Scholar 

  13. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature411, 494–498 (2001)

    Article  ADS  CAS  Google Scholar 

  14. Hannon, G. J. RNA interference. Nature418, 244–251 (2002)

    Article  ADS  CAS  Google Scholar 

  15. Aberle, H., Bauer, A., Stappert, J., Kispert, A. & Kemler, R. β-Catenin is a target for the ubiquitin-proteasome pathway. EMBO J.16, 3797–3804 (1997)

    Article  CAS  Google Scholar 

  16. Orford, K., Crockett, C., Jensen, J. P., Weissman, A. M. & Byers, S. W. Serine phosphorylation-regulated ubiquitination and degradation of β-catenin. J. Biol. Chem.272, 24735–24738 (1997)

    Article  CAS  Google Scholar 

  17. Cheshire, D. R. & Isaacs, W. B. β-Catenin signaling in prostate cancer: an early perspective. Endocr. Relat. Cancer10, 537–560 (2003)

    Article  Google Scholar 

  18. Clever, H. Wnt breakers in colon cancer. Cancer Cell5, 5–6 (2004)

    Article  Google Scholar 

  19. Moon, R. T., Bowerman, B., Boutros, M. & Perrimon, N. The promise and perils of Wnt signaling through β-catenin. Science296, 1644–1646 (2002)

    Article  ADS  CAS  Google Scholar 

  20. Chesire, D. R., Ewing, C. M., Gage, W. R. & Isaacs, W. B. In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis. Oncogene21, 2679–2694 (2002)

    Article  CAS  Google Scholar 

  21. Deng, J. et al. β-Catenin interacts with and inhibits NF-κB in human colon and breast cancer. Cancer Cell2, 323–334 (2002)

    Article  CAS  Google Scholar 

  22. Li, J. et al. Novel NEMO/IκB kinase and NF-κB target genes at the pre-B to immature B cell transition. J. Biol. Chem.276, 18579–18590 (2001)

    Article  CAS  Google Scholar 

  23. Albini, A. et al. A rapid in vitro assay for quantiating the invasive potential of tumor cells. Cancer Res.47, 3239–3245 (1987)

    CAS  PubMed  Google Scholar 

  24. Kobayashi, H. et al. Inhibition of in vitro ovarian cancer cell invasion by modulation of urokinase-type plasminogen activator and cathespin B. Cancer Res.52, 3610–3614 (1992)

    CAS  PubMed  Google Scholar 

  25. Madrid, L. V. & Baldwin, A. S. Jr Regulation of NF-κB by oncoproteins and tumor suppressor protein. Methods Mol. Biol.223, 523–532 (2003)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Hoffman for providing p50-knockout immortalized 3T3 cells; E. H. Koo and colleague for making KAI1-expressing LNCaP cells; D. A. Galloway for HPV-E6/E7 retroviral constructs; J.-T. Dong for KAI1 promoter clone; L. B. Owen-Schaub for Fas promoter reporter constructs; M.-C. Hung for mutant β-catenin constructs; K. Matsumoto for 293IL-RI cells; K. I. Kim, Y. K. Park and J. M. Lee for critical reading; and J. Hightower and M. Fisher for figure and manuscript preparation. We acknowledge support from the National R&D programme for cancer control from Ministry of Health & Welfare, Korea Research Foundation grant, and the BK21 Research Fellowship from the Ministry of Education and Human Resources Development (S.H.B.), the NIH (M.G.R., C.L.S., D.W.R.), and the Prostate Cancer Foundation (PCF) and the National Cancer Institute (NCI) (M.G.R.). M.G.R. is an HHMI Investigator.

Author information

Author notes

  1. Jung Hwa Kim, Bogyou Kim and Ling Cai: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, 151-742, South Korea

    Jung Hwa Kim, Bogyou Kim, Hee June Choi, Chin Ha Chung & Sung Hee Baek

  2. Department and School of Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California, 92093-0648, USA

    Ling Cai, Kenneth A. Ohgi & Michael G. Rosenfeld

  3. Howard Hughes Medical Institute, Department of Medicine, University of California, Los Angeles, Los Angeles, California, 90095, USA

    Chris Tran, Charlie Chen & Charles L. Sawyers

  4. Institute of Clinical Chemistry and Pathobiochemistry, Charite - Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Otmar Huber

  5. Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, San Diego, California, 92093, USA

    David W. Rose

Authors
  1. Jung Hwa Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bogyou Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ling Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hee June Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth A. Ohgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chris Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charlie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chin Ha Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Otmar Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David W. Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Charles L. Sawyers
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael G. Rosenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sung Hee Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michael G. Rosenfeld or Sung Hee Baek.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

Primary tumour weights in prostate were comparable in both control vector-expressing and KAI1-expressing cell tumours. (GIF 24 kb)

Supplementary Figure S2

Tip60 was overexpressed in LNCaP cells and immunoblot assay confirmed the expression of Tip60. Validation of specific knock-down effects of Tip60 and pontin by specific shRNA was shown. (GIF 69 kb)

Supplementary Figure S3

A constitutive active mutant of β-catenin on Tip60 was overexpressed in RWPE1 cells or 293 cells and immunoblot confirmed the overexpression of β-catenin. Other target promoter activated by Tip60 in the presence of high levels of β-catenin was shown. Increase of β-catenin expression in the nucleus did not change the localization of Tip60. (GIF 234 kb)

Supplementary Figure S4

Histone deacetylase is crucial for the repressive function of reptin. Validation of function of shRNAs against β-catenin, reptin, HDAC1, or HDAC3 by immunoblot analysis was shown. Both GST-pulldown assay and in vivo immunoprecipitation assays revealed that the crucial region of reptin for binding to HDAC1. (GIF 322 kb)

Supplementary Figure S5

The PC-3 cells were used in Matrigel invasion assay. The PC-3 cells exhibited no reduction of invaded cells in response to IL-1β but increase of Tip60 expression exhibited an 80% decrease in Matrigel invasion compared to the non-treated control. (GIF 151 kb)

Supplementary Legend (DOC 24 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J., Kim, B., Cai, L. et al. Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes. Nature 434, 921–926 (2005). https://doi.org/10.1038/nature03452

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03452

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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