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A novel nuclear role for the Vav3 nucleotide exchange factor in androgen receptor coactivation in prostate cancer

Oncogene volume 31, pages 716–727 (2012)Cite this article

Abstract

Increased androgen receptor (AR) transcriptional activity mediated by coactivator proteins may drive castration-resistant prostate cancer (CRPC) growth. Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), is overexpressed in human prostate cancers, particularly in models of CRPC progression. Vav3 coactivates AR in a Vav3 pleckstrin homology (PH) domain-dependent but GEF-independent manner. Ectopic expression of Vav3 in androgen-dependent human prostate cancer cells conferred robust castration-resistant xenograft tumor growth. Vav3 but not a Vav3 PH mutant greatly stimulated interaction between the AR amino and carboxyl termini (N–C interaction), which is required for maximal receptor transcriptional activity. Vav3 was distributed between the cytoplasm and nucleus with nuclear localization-dependent on the Vav3 PH domain. Membrane targeting of Vav3 abolished Vav3 potentiation of AR activity, whereas nuclear targeting of a Vav3 PH mutant rescued AR coactivation, suggesting that nuclear localization is an important function of the Vav3 PH domain. A nuclear role for Vav3 was further demonstrated by sequential chromatin immunoprecipitation assays, which revealed that Vav3 and AR were recruited to the same transcriptional complexes of an AR target gene enhancer. These data demonstrate the importance of Vav3 in CRPC and define a novel nuclear function of Vav3 in regulating AR activity.

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Acknowledgements

We are grateful to Dr Zafar Nawaz and his laboratory for advice on ChIP assays. We thank Drs Adena Rosenblatt, Omar Flores and Carlos Perez-Stable for helpful suggestions. Zhe Ma provided assistance with the mammalian two-hybrid assays. A National Institutes of Health Grant RO1CA132200 (to KLB) supported this work. LSL and FW were supported by US Department of Defense post-doctoral fellowship (PC060504); SR was an American Heart Association Predoctoral Fellow; CDF was supported by T32-HL007188 and AF acknowledges funding from R01GM083897.

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Author notes

  1. S Rao and L S Lyons: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA

    S Rao, C D Fahrenholtz, F Wu & K L Burnstein

  2. Nova Southeastern University, Ft Lauderdale, FL, USA

    L S Lyons

  3. Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA

    A Farooq

  4. Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA

    W Balkan

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Correspondence to K L Burnstein.

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Rao, S., Lyons, L., Fahrenholtz, C. et al. A novel nuclear role for the Vav3 nucleotide exchange factor in androgen receptor coactivation in prostate cancer. Oncogene 31, 716–727 (2012). https://doi.org/10.1038/onc.2011.273

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