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Identification of ETS-like transcription factor 4 as a novel androgen receptor target in prostate cancer cells

Oncogene volume 27, pages 4865–4876 (2008)Cite this article

Abstract

Transcriptional control by androgens via androgen receptor (AR) is strongly involved in prostate cancer development, but the critical target genes have remained elusive. We have characterized E twenty-six-like transcription factor 4 (ELK4) (also known as serum response factor accessory protein 1) as a novel AR target in human prostate cancer cells. In-silico screening identified three putative AR response elements (AREs) within −10 kb from the transcription start site of ELK4. Both ARE1 at −167/−153 and ARE2 at −481/−467 bound AR in vitro and mediated androgen induction as isolated elements in transcription assays in non-prostate cells. However, merely the ARE2 that cooperates with a proximal forkhead box A1-binding site was critical for the AR-dependent activation of ELK4 promoter in prostate cancer cells. Preferential loading of holo-AR onto the ARE2 and concomitant recruitment of RNA polymerase II onto the ELK4 promoter was confirmed in prostate cancer cells by chromatin immunoprecipitation. Database searches indicated that the expression of ELK4 is markedly increased in prostate cancers relative to normal prostates. Moreover, prostate cancer tissue immunostainings showed that nuclear ELK4 levels are significantly increased in androgen-refractory prostate cancers compared to untreated tumours. Reduction of the amount of ELK4 in LNCaP cells by RNAi retarded cell growth. In conclusion, ELK4 is a direct AR target in prostate cancer cells. Androgens may thus contribute to the growth of prostate cancer via influencing ELK4 levels.

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Acknowledgements

This work was supported by grants from the Academy of Finland, Association for International Cancer Research, Finnish Cancer Foundation, Sigrid Jusélius Foundation, Kuopio Naturalists’ Society, Helena Vuorenmies Foundation, Karjalan Sivistysseura and Finnish Union of Experts in Science. We thank Merja Räsänen for skilful technical assistance.

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  1. T Pitkänen-Arsiola

    Present address: 4Current address: Department of Biosciences/Applied Biotechnology, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.,

Authors and Affiliations

  1. Institute of Biomedicine/Medical Biochemistry, University of Kuopio, Kuopio, Finland

    H Makkonen, T Jääskeläinen, T Pitkänen-Arsiola, M Rytinki & J J Palvimo

  2. Institute of Medical Technology, University of Tampere, and Tampere University Hospital, Tampere, Finland

    K K Waltering & T Visakorpi

  3. Institute of Clinical Medicine/Clinical Microbiology, University of Kuopio, Kuopio, Finland

    M Mättö

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Correspondence to J J Palvimo.

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

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Makkonen, H., Jääskeläinen, T., Pitkänen-Arsiola, T. et al. Identification of ETS-like transcription factor 4 as a novel androgen receptor target in prostate cancer cells. Oncogene 27, 4865–4876 (2008). https://doi.org/10.1038/onc.2008.125

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