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Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer

Oncogene volume 24, pages 6765–6772 (2005)Cite this article

Abstract

Heparanase plays a critical role in the degradation of extracellular matrix and cell membrane and is frequently upregulated in malignant tumors. Transcription factor, early growth response 1 (EGR1), is closely associated with inducible transcription of the heparanase gene. We hypothesized that promoter CpG hypomethylation with increased EGR1 expression could determine heparanase expression during the pathogenesis of bladder cancer. Bladder cancer cell lines (J82, T24 and transitional cell carcinoma) significantly restored heparanase expression after 5-Aza-dC treatment. Transfection of EGR1 siRNA with T24 bladder cancer cell line significantly downregulated heparanase expression compared to the control siRNA transfection. In 54 bladder cancer and paired normal bladder samples, heparanase expression was significantly higher in bladder cancer than in normal bladder (P<0.01). We performed methylation-specific PCR targeting the CpG sites within the core-binding consensus motifs of EGR1 (GGCG) and Sp1 (GGGCGG). Methylation prevalence was significantly higher in normal bladder than in bladder cancer (P<0.05) and inversely correlated with heparanase expression (P=0.055). In the total series of bladder cancer and normal bladder samples, the combination of promoter CpG methylation and EGR1 expression regulated heparanase expression in a stepwise manner, where heparanase expression was the lowest in methylation-positive and EGR1-negative samples and the highest in methylation-negative and EGR1-positive samples. To our knowledge, this is the first study demonstrating that increased heparanase expression during the pathogenesis of bladder cancer is due to promoter hypomethylation and transcription factor EGR1.

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Acknowledgements

This work was supported by grants RO1AG21418, T32DK07790, RO1CA1018447 and RO1TW006215 from NIH, and the VA REAP award and Merit Review grants.

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Authors and Affiliations

  1. Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California, 4150 Clement Street, San Francisco, 94121, CA, USA

    Tatsuya Ogishima, Julia E Breault, Hideki Enokida, Shinji Urakami, Takashi Tokizane, Toshifumi Kawakami, Christopher J Kane, Peter R Carroll & Rajvir Dahiya

  2. Department of Urology, Shimane University School of Medicine, Izumo, 693-0085, Japan

    Hiroaki Shiina, Masaharu Terashima, Satoshi Honda & Mikio Igawa

  3. Department of Urology, University of São Paulo School of Medicine, São Paulo, Brazil

    Leopoldo A Ribeiro-Filho

  4. Department of Urology, Juntendo University School of Medicine, Tokyo, 113-0082, Japan

    Tatsuya Ogishima & Makoto Fujime

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  1. Tatsuya Ogishima
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Correspondence to Rajvir Dahiya.

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Ogishima, T., Shiina, H., Breault, J. et al. Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. Oncogene 24, 6765–6772 (2005). https://doi.org/10.1038/sj.onc.1208811

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