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Cyclin D3 action in androgen receptor regulation and prostate cancer

Oncogene volume 27, pages 3111–3121 (2008)Cite this article

Abstract

Prostate cancer (PCa) cell proliferation is dependent on activation of the androgen receptor (AR), a ligand-dependent transcription factor. AR activation controls G1–S phase progression through fostering enhanced translation of the D-type cyclins, which promote cell cycle progression through activation of CDK4/6. However, the D-type cyclins harbor additional, CDK4/6 kinase-independent, functions through manipulation of transcription factors, including AR. It was previously established that cyclins D1 and D3 have the potential to modulate AR, and with regard to cyclin D1, disruption of this function occurs in human tumors. Therefore, it was essential to interrogate cyclin D3 function in this tumor type. Here, we show that cyclin D3 is found in association with AR in PCa cells, as mediated through a conserved motif. Cyclin D3 functions to attenuate AR activity through defined mechanisms that include modulation of ligand-dependent conformational changes and modulation of chromatin binding activity. Accumulated cyclin D3 slows cell proliferation in AR-dependent cells, thus suggesting that androgen-induced D-type cyclin production serves to temper the mitogenic response to androgen. Supporting this hypothesis, it is shown that cyclin D3 expression is reduced in primary PCas as a function of tumor grade, and inversely correlates with the proliferative index. In total, these data identify cyclin D3 as a critical modulator of the androgen response, whose deregulation may foster unchecked AR activity in PCa.

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Acknowledgements

We thank both K Knudsen and E Knudsen laboratories for their technical and intellectual input and Sandy Schwemberger and George Babcock for flow cytometry assistance. This work was supported by CA099996 and CA116777 (to KEK). NAO and CJB were supported by NIEHS Training Grant T32-ES07250. CESC and LMM were supported by T32-CA117846.

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Authors and Affiliations

  1. Department of Cell and Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    N A Olshavsky, E M Groh, C E S Comstock, L M Morey, Y Wang & K E Knudsen

  2. Department of Pathology and Laboratory Medicine, University of Utah, Salt Lake City, UT, USA

    M P Revelo

  3. Laboratory of Molecular Carcinogenesis, NIEHS, Research Triangle Park, NC, USA

    C Burd

  4. UC Cancer Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    J Meller & K E Knudsen

  5. Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    J Meller

  6. Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    K E Knudsen

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  1. N A Olshavsky
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  2. E M Groh
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  3. C E S Comstock
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  4. L M Morey
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  7. C Burd
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  9. K E Knudsen
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Correspondence to K E Knudsen.

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

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Olshavsky, N., Groh, E., Comstock, C. et al. Cyclin D3 action in androgen receptor regulation and prostate cancer. Oncogene 27, 3111–3121 (2008). https://doi.org/10.1038/sj.onc.1210981

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