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The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis

Nature volume 428, pages 328–332 (2004)Cite this article

Abstract

Gliomas are the most common primary tumours of the central nervous system, with nearly 15,000 diagnosed annually in the United States and a lethality approaching 80% within the first year of glioblastoma diagnosis1. The marked induction of angiogenesis in glioblastomas suggests that it is a necessary part of malignant progression2; however, the precise molecular mechanisms underlying the regulation of brain tumour growth and angiogenesis remain unresolved. Here we report that a candidate tumour suppressor gene, ING4, is involved in regulating brain tumour growth and angiogenesis. Expression of ING4 is significantly reduced in gliomas as compared with normal human brain tissue, and the extent of reduction correlates with the progression from lower to higher grades of tumours. In mice, xenografts of human glioblastoma U87MG, which has decreased expression of ING4, grow significantly faster and have higher vascular volume fractions than control tumours. We show that ING4 physically interacts with p65 (RelA) subunit of nuclear factor NF-κB, and that ING4 regulates brain tumour angiogenesis through transcriptional repression of NF-κB-responsive genes. These results indicate that ING4 has an important role in brain tumour pathogenesis.

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Figure 1: Expression of ING4 is downregulated in human gliomas and is negatively correlated with their progression.
Figure 2: ING4 regulates tumour growth and angiogenesis in vivo.
Figure 3: Downregulation of the ING4 gene activates the angiogenic IL8 gene in vitro and in vivo.
Figure 4: Interaction of ING4 and NF-κB decreases NF-κB binding activity and inhibits transactivation of NF-κB-responsive genes.
Figure 5: ING4-mediated regulation of IL-8 significantly influences brain tumour growth and angiogenesis.

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Acknowledgements

We thank E. di Tomaso, P. Vitello, S. Roberge and A. Merkulova for technical assistance; and B. Seed, D. Fukamura and D. Duda for comments on the manuscript. This work was supported by grants from the National Cancer Institute.

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Authors and Affiliations

  1. Edwin L. Steele Laboratory for Tumour Biology, Department of Radiation Oncology Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA

    Igor Garkavtsev, Sergey V. Kozin, Lei Xu, Frank Winkler, Edward Brown & Rakesh K. Jain

  2. The Brain Tumour Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA

    Olga Chernova & Gene H. Barnett

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  1. Igor Garkavtsev
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  2. Sergey V. Kozin
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  3. Olga Chernova
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Correspondence to Igor Garkavtsev.

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Garkavtsev, I., Kozin, S., Chernova, O. et al. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 428, 328–332 (2004). https://doi.org/10.1038/nature02329

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