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:

The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways

Abstract

CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins1,2,3,4,5,6,7,8,9,10,11,12. The relationship between CHIP and tumour progression, however, has not been elucidated. Here, we show that CHIP suppresses tumour progression in human breast cancer by inhibiting oncogenic pathways. CHIP levels were negatively correlated with the malignancy of human breast tumour tissues. In a nude mouse xenograft model, tumour growth and metastasis were significantly inhibited by CHIP expression. In contrast, knockdown of CHIP (shCHIP) in breast cancer cells resulted in rapid tumour growth and metastastic phenotypes in mice. In cell-based experiments, anchorage-independent growth and invasiveness of shCHIP cells was significantly elevated due to increased expression of Bcl2, Akt1, Smad and Twist. Proteomic analysis identified the transcriptional co-activator SRC-3 (refs 13, 14, 15, 16, 17, 18, 19) as a direct target for ubiquitylation and degradation by CHIP. Knocking down SRC-3 in shCHIP cells reduced the expression of Smad and Twist, and suppressed tumour metastasis in vivo. Conversely, SRC-3 co-expression prevented CHIP-induced suppression of metastasis formation. These observations demonstrate that CHIP inhibits anchorage-independent cell growth and metastatic potential by degrading oncogenic proteins including SRC-3.

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

Access options

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

Figure 1: Decreased CHIP expression in malignant breast tumour tissues.
Figure 2: CHIP suppresses tumour growth in a mouse xenograft model.
Figure 3: Downregulation of CHIP expression results in the malignant transformation of MCF-7 cells.
Figure 4: CHIP targets SRC-3 for ubiquitylation and degradation.
Figure 5: SRC-3 is the downstream regulator of CHIP during cancer metastasis.

Similar content being viewed by others

References

  1. Esser, C., Alberti, S. & Hohfeld, J. Cooperation of molecular chaperones with the ubiquitin/proteasome system. Biochim.Biophys. Acta 1695, 171–188 (2004).

    Article  CAS  Google Scholar 

  2. Ballinger, C. A. et al. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol. Cell. Biol. 19, 4535–4545 (1999).

    Article  CAS  Google Scholar 

  3. Connell, P. et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nature Cell Biol. 3, 93–96 (2001).

    Article  CAS  Google Scholar 

  4. McDonough, H. & Patterson, C. CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones. 8, 303–308 (2003).

    Article  CAS  Google Scholar 

  5. Meacham, G. C., Patterson, C., Zhang, W., Younger, J. M. & Cyr, D. M. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nature Cell Biol. 3, 100–105 (2001).

    Article  CAS  Google Scholar 

  6. Tateishi, Y. et al. Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor. EMBO J. 23, 4813–4823 (2004).

    Article  CAS  Google Scholar 

  7. Xu, W. et al. Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc. Natl Acad. Sci. USA 99, 12847–12852 (2002).

    Article  CAS  Google Scholar 

  8. Esser, C., Scheffner, M. & Hohfeld, J. The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J. Biol. Chem. 280, 27443–27448 (2005).

    Article  CAS  Google Scholar 

  9. Xin, H. et al. CHIP controls the sensitivity of transforming growth factor-β signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. J. Biol. Chem. 280, 20842–20850 (2005).

    Article  CAS  Google Scholar 

  10. Kamynina, E., Kauppinen, K., Duan, F., Muakkassa, N. & Manor, D. Regulation of proto-oncogenic dbl by chaperone-controlled, ubiquitin-mediated degradation. Mol. Cell. Biol. 27, 1809–1822 (2007).

    Article  CAS  Google Scholar 

  11. Fan, M., Park, A. & Nephew, K. P. CHIP (carboxyl terminus of Hsc70-interacting protein) promotes basal and geldanamycin-induced degradation of estrogen receptor-α. Mol. Endocrinol. 19, 2901–2914 (2005).

    Article  CAS  Google Scholar 

  12. Tateishi, Y. et al. Turning off estrogen receptor β-mediated transcription requires estrogen-dependent receptor proteolysis. Mol. Cell. Biol. 26, 7966–7976 (2006).

    Article  CAS  Google Scholar 

  13. Wu, R. C. et al. Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic reponses to multiple cellular signaling pathways. Mol Cell 15, 937–949 (2004).

    Article  CAS  Google Scholar 

  14. Anzick, S. L. et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277, 965–968 (1997).

    Article  CAS  Google Scholar 

  15. Chen, H. et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90, 569–580 (1997).

    Article  CAS  Google Scholar 

  16. Takeshita, A., Cardona, G. R., Koibuchi, N., Suen, C. S. & Chin, W. W. TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1. J. Biol. Chem. 272, 27629–27634 (1997).

    Article  CAS  Google Scholar 

  17. Torchia, J. et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677–684 (1997).

    Article  CAS  Google Scholar 

  18. Li, H., Gomes, P. J. & Chen, J. D. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc. Natl Acad. Sci. USA 94, 8479–8484 (1997).

    Article  CAS  Google Scholar 

  19. Hudelist, G. et al. Expression of sex steroid receptors and their co-factors in normal and malignant breast tissue: AIB1 is a carcinoma-specific co-activator. Breast Cancer Res. Treatment 78, 193–204 (2003).

    Article  CAS  Google Scholar 

  20. Cory, S. & Adams, J. M. The Bcl2 family: regulators of the cellular life-or-death switch. Nature Rev. Cancer 2, 647–656 (2002).

    Article  CAS  Google Scholar 

  21. Adams, J. M. & Cory, S. The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322–1326 (1998).

    Article  CAS  Google Scholar 

  22. Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    Article  CAS  Google Scholar 

  23. Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001).

    Article  CAS  Google Scholar 

  24. Attisano, L. & Wrana, J. L. Signal transduction by the TGF-β superfamily. Science 296, 1646–1647 (2002).

    Article  CAS  Google Scholar 

  25. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    Article  CAS  Google Scholar 

  26. Lee, J. M., Dedhar, S., Kalluri, R. & Thompson, E. W. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J. Cell Biol. 172, 973–981 (2006).

    Article  CAS  Google Scholar 

  27. Wu, R. C., Feng, Q., Lonard, D. M. & O'Malley, B. W. SRC-3 co-activator functional lifetime is regulated by a phospho-dependent ubiquitin time clock. Cell 129, 1125–1140 (2007).

    Article  CAS  Google Scholar 

  28. Kuang, S. Q. et al. AIB1/SRC-3 deficiency affects insulin-like growth factor I signaling pathway and suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. Cancer Res. 64, 1875–1885 (2004).

    Article  CAS  Google Scholar 

  29. Thuault, S. et al. Transforming growth factor-β employs HMGA2 to elicit epithelial-mesenchymal transition. J. Cell Biol. 174, 175–183 (2006).

    Article  CAS  Google Scholar 

  30. Izzi, L. & Attisano, L. Regulation of the TGFβ signalling pathway by ubiquitin-mediated degradation. Oncogene 23, 2071–2078 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a nuclear system to decipher operation code (DECODE) and Targeted Proteins Research Program (TPRP) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

Author information

Authors and Affiliations

Authors

Contributions

M. Kajiro. and R.H. performed most of the experiments; K.K., Y.Y., Y.K., Y.S., H.T., S. H. and M. Kurosumi. analysed human tissue samples; Y.N., K.S., I.I., S.O. and M. Kawano contributed to the animal experiments; K.K. and J.Y. planned the project.

Corresponding author

Correspondence to Junn Yanagisawa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 2298 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kajiro, M., Hirota, R., Nakajima, Y. et al. The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways. Nat Cell Biol 11, 312–319 (2009). https://doi.org/10.1038/ncb1839

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1839

This article is cited by

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