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Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation

Oncogene volume 30, pages 2207–2218 (2011)Cite this article

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Abstract

The transcriptional activity of the androgen receptor (AR) is regulated by both ligand binding and post-translational modifications, including acetylation and small ubiquitin-like modifier (SUMO)ylation. Histone deacetylases (HDACs) are known to catalyze the removal of acetyl groups from both histones and non-histone proteins. In this study, we report that HDAC4 binds to and inhibits the activity of the AR. This inhibition was found to depend on the SUMOylation, instead of deacetylation, of the AR. Consistently, HDAC4 increases the level of AR SUMOylation in both whole-cell and cell-free assay systems, raising the possibility that the deacetylase may act as an E3 ligase for AR SUMOylation. Knock down of HDAC4 increases the activity of endogenous AR and androgen induction of prostate-specific antigen expression and prostate cancer cell growth, which is associated with decreased SUMOylation of the receptor. Overall, the studies identify HDAC4 as a positive regulator for AR SUMOylation, revealing a deacetylase-independent mechanism of HDAC action in prostate cancer cells.

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Acknowledgements

We thank Drs XJ Yang for HDAC4 vector, RJ Matusik for probasin-based AR reporter genes, PR Rennie for the PSA-based reporter gene, G Jenster for GST-AR-NT construct, JJ Palvimo for AR SUMOylation mutants and AP Lieberman for AR acetylation mutants. The work was supported by the Public Health Service Grants CA93666 and CA111334 (WB), a DOD Prostate Cancer Grant DAMD17-02-1-0140 (WB) and Grants 09KT-03 and 06BCBG1 (W.B) from the Florida Department of Health.

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Author notes

  1. Y Yang

    Present address: 5Current address: Medical College of Georgia Cancer Center, Augusta, GA, USA.,

  2. Y Yang and A K-W Tse: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, FL, USA

    Y Yang, A K-W Tse, P Li, Q Ma, S Xiang, S V Nicosia, X Zhang & W Bai

  2. Department of Oncological Sciences, University of South Florida College of Medicine, Tampa, FL, USA

    S V Nicosia, E Seto, X Zhang & W Bai

  3. Experimental Therapeutics, H Lee Moffitt Cancer Center, Tampa, FL, USA

    S V Nicosia

  4. Programs of Molecular Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USA

    E Seto, X Zhang & W Bai

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Correspondence to W Bai.

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Yang, Y., Tse, AW., Li, P. et al. Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation. Oncogene 30, 2207–2218 (2011). https://doi.org/10.1038/onc.2010.600

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  • DOI: https://doi.org/10.1038/onc.2010.600

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