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Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

Oncogene volume 26, pages 1028–1037 (2007)Cite this article

Abstract

Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance of E2F3 overexpression in bladder cancer development. Knockdown of E2F3 expression in bladder cells containing the 6p22 amplicon strongly reduced the extent of bromodeoxyuridine (BrdU) incorporation and the rate of cellular proliferation. In contrast, knockdown of CDKAL1/FLJ20342, another proposed oncogene, from this amplicon had no effect. Expression cDNA microarray analysis on bladder cancer cells following E2F3 knockdown was then used to identify genes regulated by E2F3, leading to the identification of known E2F3 targets such as Cyclin A and CDC2 and novel targets including pituitary tumour transforming gene 1, Polo-like kinase 1 (PLK1) and Caveolin-2. For both bladder and prostate cancer, we have proposed that E2F3 protein overexpression may cooperate with removal of the E2F inhibitor retinoblastoma tumor suppressor protein (pRB) to drive cellular proliferation. In support of this model, we found that ectopic expression of E2F3a enhanced the BrdU incorporation, a marker of cellular proliferation rate, of prostate cancer DU145 cells, which lack pRB, but had no effect on the proliferation rate of PC3 prostate cancer cells that express wild-type pRB. BrdU incorporation in PC3 cells could, however, be increased by overexpressing E2F3a in cells depleted of pRB. When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer.

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Acknowledgements

This work was funded by Cancer Research UK. AY Olsson is funded by EU Marie Curie fellowship grant and CS Cooper by the Grand Charity of Freemasons. The technical assistance of Jenny Titley for running the flow cytometry is acknowledged.

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Author notes

  1. A Feber

    Present address: Department of Oncology/Haematology, Mount Sinai School of Medicine, New York, USA

Authors and Affiliations

  1. Section of Molecular Carcinogenesis, Institute of Cancer Research, Male Urological Cancer Research Centre, Sutton, Surrey, UK

    A Y Olsson, A Feber, S Edwards, I Giddings, S Merson & C S Cooper

  2. CRUK Centre of Cancer Therapeutics, Institute of Cancer Research, Male Urological Cancer Research Centre, Sutton, Surrey, UK

    R te Poele

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Correspondence to A Y Olsson.

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

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Olsson, A., Feber, A., Edwards, S. et al. Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells. Oncogene 26, 1028–1037 (2007). https://doi.org/10.1038/sj.onc.1209854

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