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Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells

Oncogene volume 33, pages 26–33 (2014)Cite this article

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Abstract

The androgen receptor (AR) has a vital role in the onset and progression of prostate cancer by promoting G1-S progression, possibly by functioning as a licensing factor for DNA replication. We here report that low dose 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, induces mitotic arrest in prostate cancer cells involving activation of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein) and degradation of the AR. Depletion of the AR by small interfering RNA (siRNA) eliminates 2-ME-induced arrest and introducing AR into PC3-M cells confers 2-ME-induced mitotic arrest. Knockdown of CHIP or MDM2 (mouse homolog of double minute 2 protein) individually or in combination reduced AR degradation and abrogated M phase arrest induced by 2-ME. Our data link AR degradation via ubiquitination to mitotic arrest. Targeting the AR by activating E3 ligases such as CHIP represents a novel strategy for the treatment of prostate cancer.

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Acknowledgements

This work was supported, in whole or in part, by the National Institutes of Health grant 5R01CA142823-02 (to J. M. L.) as well as the Charles R. Burnett Jr and W. Griffin Burnett Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Virginia Health Sciences Center, University of Virginia School of Medicine, Charlottesville, VA, USA

    S Sarkar & J M Larner

  2. Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA

    D L Brautigan

  3. Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA

    D L Brautigan & S J Parsons

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  1. S Sarkar
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  2. D L Brautigan
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Correspondence to J M Larner.

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Sarkar, S., Brautigan, D., Parsons, S. et al. Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells. Oncogene 33, 26–33 (2014). https://doi.org/10.1038/onc.2012.561

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