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Tumor suppressor p53 regulates heparanase gene expression

Oncogene volume 25, pages 3939–3947 (2006)Cite this article

Abstract

Mammalian heparanase degrades heparan sulfate, the most prominent polysaccharide of the extracellular matrix. Causal involvement of heparanase in tumor progression is well documented. Little is known, however, about mechanisms that regulate heparanase gene expression. Mutational inactivation of tumor suppressor p53 is the most frequent genetic alteration in human tumors. p53 is a transcription factor that regulates a wide variety of cellular promoters. In this study, we demonstrate that wild-type (wt) p53 binds to heparanase promoter and inhibits its activity, whereas mutant p53 variants failed to exert an inhibitory effect. Moreover, p53-H175R mutant even activated heparanase promoter activity. Elimination or inhibition of p53 in several cell types resulted in a significant increase in heparanase gene expression and enzymatic activity. Trichostatin A abolished the inhibitory effect of wt p53, suggesting the involvement of histone deacetylation in negative regulation of the heparanase promoter. Altogether, our results indicate that the heparanase gene is regulated by p53 under normal conditions, while mutational inactivation of p53 during cancer development leads to induction of heparanase expression, providing a possible explanation for the frequent increase of heparanase levels observed in the course of tumorigenesis.

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Acknowledgements

We thank Mrs Irit Cohen (Hadassah-University Medical Center, Jerusalem) for help with the ChIP assay, Professors Moshe Oren (Weizmann Institute of Science, Israel), Karen Vousden (Beaston Institute, UK), D Trono, (University of Geneva, Switzerland) and Reuven Agami (The Netherland Cancer Institute) for plasmids. This study was supported by a Postdoctoral Fellowship from the Israel Cancer Research Fund, by a Scholarship from the Women's Group of the Mexican Friends of the Hebrew University (awarded to LB) and by grants from the US Army (Award #W81XWH-04-1-0235), the Israel Science Foundation (Grant 532/02), the Israel Cancer Association, the Prostate Cancer Foundation, and by United States Public Service Grant RO1 CA 106456 from NCI, National Institutes of Health.

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Authors and Affiliations

  1. Department of Oncology, Hadassah-University Medical Center, Jerusalem, Israel

    L Baraz, M Elkin & T Peretz

  2. Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem,, Israel

    Y Haupt

  3. Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

    I Vlodavsky

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  1. L Baraz
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Correspondence to I Vlodavsky.

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Baraz, L., Haupt, Y., Elkin, M. et al. Tumor suppressor p53 regulates heparanase gene expression. Oncogene 25, 3939–3947 (2006). https://doi.org/10.1038/sj.onc.1209425

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