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Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer

Oncogene volume 28, pages 1016–1027 (2009)Cite this article

Abstract

Regulation of the androgen receptor (AR) is critical to prostate cancer (PCa) development; therefore, AR is the first line therapeutic target for disseminated tumors. Cell cycle-dependent accumulation of cyclin D1 negatively modulates the transcriptional regulation of AR through discrete, CDK4-independent mechanisms. The transcriptional corepressor function of cyclin D1 resides within a defined motif termed repressor domain (RD), and it was hypothesized that this motif could be utilized as a platform to develop new strategies for blocking AR function. Here, we demonstrate that expression of the RD peptide is sufficient to disrupt AR transcriptional activation of multiple, prostate-specific AR target genes. Importantly, these actions are sufficient to specifically inhibit S-phase progression in AR-positive PCa cells, but not in AR-negative cells or tested AR-positive cells of other lineages. As expected, impaired cell cycle progression resulted in a suppression of cell doubling. Additionally, cell death was observed in AR-positive cells that maintain androgen dependence and in a subset of castrate-resistant PCa cells, dependent on Akt activation status. Lastly, the ability of RD to cooperate with existing hormone therapies was examined, which revealed that RD enhanced the cellular response to an AR antagonist. Together, these data demonstrate that RD is sufficient to disrupt AR-dependent transcriptional and proliferative responses in PCa, and can enhance efficacy of AR antagonists, thus establishing the impetus for development of RD-based mimetics.

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Acknowledgements

We thank the K Knudsen lab for critical input, especially SM Godoy Tundidor; S Schwemberger, S Fox and M Faradaugh for technical assistance, and the E Knudsen laboratory for commentary. This work was supported by NIH grants CA099996 and CA116777 (to KEK); CA015776, CA062269, CA112532 (to SMH). LMM was supported by training grant T32-CA117846.

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  1. M J Schiewer and L M Morey: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA

    M J Schiewer & K E Knudsen

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

    L M Morey & S-M Ho

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

    C J Burd

  4. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA

    Y Liu & D E Merry

  5. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    D E Merry & K E Knudsen

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

    S-M Ho

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

    S-M Ho

  8. Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA

    K E Knudsen

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Schiewer, M., Morey, L., Burd, C. et al. Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer. Oncogene 28, 1016–1027 (2009). https://doi.org/10.1038/onc.2008.446

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