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.

  • Article
  • Published:

Suppression of tumor growth through disruption of hypoxia-inducible transcription

Nature Medicine volume 6, pages 1335–1340 (2000)Cite this article

Abstract

Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Strategies to treat tumors have been developed in which tumor cells are targeted with drugs or gene-therapy vectors specifically activated under hypoxic conditions. Here we report a different approach, in which the normal transcriptional response to hypoxia is selectively disrupted. Our data indicate that specific blockade of the interaction of hypoxia-inducible factor with the CH1 domain of its p300 and CREB binding protein transcriptional coactivators leads to attenuation of hypoxia-inducible gene expression and diminution of tumor growth. Thus, disrupting the normal co-activational response to hypoxia may be a new and useful therapeutic strategy.

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: Structural requirements for HIF-1α interaction with p300/CBP.
Figure 2: In vivo effects of CH1 or TAD-C polypeptide overexpression.
Figure 3: Specificity of TAD-C polypeptide effects.
Figure 4: Anti-tumor effects of TAD-C polypeptide expression.
Figure 5: The anti-tumor effect of TAD-C can be rescued by CH1-independent HIF-1α.

Similar content being viewed by others

References

  1. Semenza, G.L. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu. Rev. Cell. Dev. Biol. 15, 551–578 (1999).

    Article  CAS  Google Scholar 

  2. Wang, G.L., Jiang, B.H., Rue, E.A. & Semenza, G.L. Hypoxia-inducible factor 1 is a basic-HLH-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 92, 5510–5514 (1995).

    Article  CAS  Google Scholar 

  3. Salceda, S. & Caro, J. HIF-1α protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J. Biol. Chem. 272, 22642–22647 (1997).

    Article  CAS  Google Scholar 

  4. Huang, L.E., Arany, Z., Livingston, D.M. & Bunn, H.F. Activation of HIF depends primarily upon redox-sensitive stabilization of its α subunit. J. Biol. Chem. 271, 32253–32259 (1996).

    Article  CAS  Google Scholar 

  5. Maxwell, P.H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    Article  CAS  Google Scholar 

  6. Cockman, M.E. et al. HIF-α binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J. Biol. Chem. 275, 25733–25741 (2000).

    Article  CAS  Google Scholar 

  7. Ohh, M. et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel-Lindau protein. Nature Cell Biol. 2, 423–427 (2000).

    Article  CAS  Google Scholar 

  8. Jiang, B.H., Semenza, G.L., Bauer, C. & Marti, H.H. HIF-1 levels vary exponentially over a physiologically relevant range of O2 tension. Am. J. Physiol. 271, C1172–1180 (1996).

    Article  CAS  Google Scholar 

  9. Jiang, B.H., Rue, E., Wang, G.L., Roe, R. & Semenza, G.L. Dimerization, DNA binding, and transactivation properties of HIF-1. J. Biol. Chem. 271, 17771–17778 (1996).

    Article  CAS  Google Scholar 

  10. Arany, Z. et al. An essential role for p300/CBP in the cellular response to hypoxia. Proc. Natl. Acad. Sci. USA 93, 12969–12973 (1996).

    Article  CAS  Google Scholar 

  11. Ebert, B.L. & Bunn, H.F. Regulation of transcription by hypoxia requires a multiprotein complex that includes HIF-1, an adjacent transcription factor, and p300/CREB binding protein. Mol. Cell. Biol. 18, 4089–4096 (1998).

    Article  CAS  Google Scholar 

  12. Kallio, P.J. et al. Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 co-activator by the HIF-1α. EMBO J. 17, 6573–6586 (1998).

    Article  CAS  Google Scholar 

  13. Carrero, P. et al. Redox-regulated recruitment of the transcriptional co-activators CREB-binding protein and SRC-1 to HIF-1α. Mol. Cell. Biol. 20, 402–415 (2000).

    Article  CAS  Google Scholar 

  14. Semenza, G.L. & Wang, G.L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12, 5447–5454 (1992).

    Article  CAS  Google Scholar 

  15. Nordsmark, M., Bentzen, S.M. & Overgaard, J. Measurement of human tumour oxygenation status by a polarographic needle electrode. An analysis of inter- and intratumour heterogeneity. Acta Oncol. 33, 383–389 (1994).

    Article  CAS  Google Scholar 

  16. Helmlinger, G., Yuan, F., Dellian, M. & Jain, R.K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med. 3, 177–182 (1997).

    Article  CAS  Google Scholar 

  17. Brown, J.M. Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies. Mol. Med. Today. 6, 157–162 (2000).

    Article  CAS  Google Scholar 

  18. Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).

    Article  CAS  Google Scholar 

  19. Zhong, H. et al. Overexpression of HIF-1α in common human cancers and their metastases. Cancer Res. 59, 5830–5835 (1999).

    CAS  PubMed  Google Scholar 

  20. Hockel, M. et al. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 56, 4509–4515 (1996).

    CAS  PubMed  Google Scholar 

  21. Brizel, D.M. et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56, 941–943 (1996).

    CAS  PubMed  Google Scholar 

  22. Zeman, E. M., Brown, J. M., Lemmon, M. J., Hirst, V. K. & Lee, W. W. SR-4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int. J. Radiat. Oncol. Biol. Phys. 12, 1239–1242 (1986).

    Article  CAS  Google Scholar 

  23. Binley, K., Iqball, S., Kingsman, A., Kingsman, S. & Naylor, S. An adenoviral vector regulated by hypoxia for the treatment of ischaemic disease and cancer. Gene Ther. 6, 1721–1727 (1999).

    Article  CAS  Google Scholar 

  24. Shibata, T., Giaccia, A.J. & Brown, J.M. Development of a hypoxia-responsive vector for tumor-specific gene therapy. Gene Ther. 7, 493–498 (2000).

    Article  CAS  Google Scholar 

  25. Jiang, B.H., Zheng, J.Z., Leung, S.W., Roe, R. & Semenza, G.L. Transactivation and inhibitory domains of HIF-1α. Modulation of transcriptional activity by oxygen tension. J. Biol. Chem. 272, 19253–19260 (1997).

    Article  CAS  Google Scholar 

  26. Wilson, I. A. et al. Identical short peptide sequences in unrelated proteins can have different conformations: a testing ground for theories of immune recognition. Proc. Natl. Acad. Sci. USA 82, 5255–5259 (1985).

    Article  CAS  Google Scholar 

  27. Chakravarti, D. et al. Role of CBP/P300 in nuclear receptor signalling. Nature 383, 99–103 (1996).

    Article  CAS  Google Scholar 

  28. Oliner, J.D., Andresen, J.M., Hansen, S.K., Zhou, S. & Tjian, R. SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein. Genes Dev. 10, 2903–2911 (1996).

    Article  CAS  Google Scholar 

  29. Yao, T.P., Ku, G., Zhou, N., Scully, R. & Livingston, D.M. The nuclear hormone receptor co-activator SRC-1 is a specific target of p300. Proc. Natl. Acad. Sci. USA 93, 10626–10631 (1996).

    Article  CAS  Google Scholar 

  30. Bhattacharya, S. et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-α. Nature 383, 344–347 (1996).

    Article  CAS  Google Scholar 

  31. Carmeliet, P. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

    Article  CAS  Google Scholar 

  32. Ryan, H.E., Lo, J. & Johnson, R.S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J 17, 3005–3015 (1998).

    Article  CAS  Google Scholar 

  33. Maxwell, P.H. et al. HIF-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl. Acad. Sci. USA 94, 8104–8109 (1997).

    Article  CAS  Google Scholar 

  34. Ryan, H.E. et al. HIF-1α is a positive factor in solid tumor growth. Cancer Res. 60, 4010–015 (2000).

    CAS  PubMed  Google Scholar 

  35. Zhong, H. et al. Modulation of HIF-1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 60, 1541–1545 (2000).

    CAS  PubMed  Google Scholar 

  36. Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391–396 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Jiang, B.H., Rue, E., Wang, G.L., Roe, R. & Semenza, G.L. Dimerization, DNA binding, and transactivation properties of HIF-1. J. Biol. Chem. 271, 17771–17778 (1996).

    Article  CAS  Google Scholar 

  38. Kamei, Y. et al. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85, 403–414 (1996).

    Article  CAS  Google Scholar 

  39. Horvai, A.E. et al. Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300. Proc. Natl. Acad. Sci. USA 94, 1074–1079 (1997).

    Article  CAS  Google Scholar 

  40. Foster, B.A., Coffey, H.A., Morin, M.J. & Rastinejad, F. Pharmacological rescue of mutant p53 conformation and function. Science 286, 2507–2510 (1999).

    Article  CAS  Google Scholar 

  41. Olumi, A.F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

  42. Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998).

    Article  CAS  Google Scholar 

  43. Ausubel, F.M. et al. (eds.) Current Protocols in Molecular Biology (Wiley-Interscience, New York, 1988).

    Google Scholar 

  44. LaVallie, E.R. et al. A thioredoxin gene fusion expression system that circumvents inclusion body formation in the E. coli cytoplasm. Biotechnology (NY) 11, 187–193 (1993).

    CAS  Google Scholar 

  45. Bhattacharya, S. et al. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 13, 64–75 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Mulligan for retroviral vectors; and L. Sambucetti, S. Zabludoff, D. France and S. Bhattacharya for their advice. This work was supported by grants from the Novartis/DFCI Drug Discovery Program (to D.M.L.), and the Howard Hughes Medical Institute (to A.L.K. and W.G.K.).

Author information

Authors and Affiliations

  1. The Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Andrew L. Kung, Stream Wang, Jeffery M. Klco, William G. Kaelin & David M. Livingston

Authors
  1. Andrew L. Kung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stream Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffery M. Klco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William G. Kaelin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David M. Livingston
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. Livingston.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kung, A., Wang, S., Klco, J. et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 6, 1335–1340 (2000). https://doi.org/10.1038/82146

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/82146

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