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Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer

Oncogene volume 27, pages 2877–2885 (2008)Cite this article

Abstract

Deregulated expression of ETS transcription factors has emerged as an important event in prostate cancer pathogenesis. Here we show that the expression of epithelial-specific ETS (ESE)-3 factor is frequently reduced at the RNA and protein level in prostate cancer clinical samples compared to normal prostate. In PC3 and DU145 cells, ESE-3 was silenced by methylation of an evolutionarily conserved CpG site in its promoter and treatment with 5-aza-2′-deoxycytidine restored its expression. In a prostate epithelial cell transformation model, methylation of this site was inversely correlated with ESE-3 expression and occurred only in Ras-transformed and tumorigenic cells and not in normal and immortalized cells suggesting that ESE-3 silencing was functionally linked to oncogenic transformation. Consistent with a tumor suppressor function, re-expression of ESE-3 in prostate cancer cells inhibited clonogenic survival and induced apoptotic cell death. ESE-3 increased the level of procaspase-3, a key element in the apoptotic cascade. This effect was mediated at the transcriptional level by direct binding of ESE-3 to the caspase-3 promoter. Collectively, our findings implicate ESE-3 as a candidate tumor suppressor in prostate cancer. Decreased expression of ESE-3 may result in loss of important regulatory mechanisms in prostate epithelial cells and contribute to the pathogenesis of prostate cancer.

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Acknowledgements

This work was supported by grants from Swiss Cancer League and the Tessin Foundation for Cancer Research to GMC and Compagnia di San Paolo, Turin, IT, to GC. RC, AM and MMG were supported by fellowships from the San Salvatore Foundation, ESO and FIRC, respectively. RC is enrolled in the PhD program in Pharmaceutical Sciences of the University of Geneva, Switzerland. We thank WC Hahn for the immortalized and transformed PrECs, A Tugores for the pRc/CMV-ESE3b-FLAG plasmid and anti-ESE-3 antibody, DK Watson for the pSGK-ETS-2 plasmid, AG Yakovlev for the pGL3-CASP3 plasmid.

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Author notes

  1. R Cangemi and A Mensah: These two authors have contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    R Cangemi, A Mensah, V Albertini, A Jain, C V Catapano & G M Carbone

  2. Laboratory of Cancer Genomics, Fondo Edo Tempia, Biella, Italy

    M Mello-Grand & G Chiorino

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  1. R Cangemi
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  2. A Mensah
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  3. V Albertini
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  4. A Jain
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  5. M Mello-Grand
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  6. G Chiorino
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  7. C V Catapano
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  8. G M Carbone
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Correspondence to G M Carbone.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Cangemi, R., Mensah, A., Albertini, V. et al. Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer. Oncogene 27, 2877–2885 (2008). https://doi.org/10.1038/sj.onc.1210953

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