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C/EBPα redirects androgen receptor signaling through a unique bimodal interaction

Oncogene volume 29, pages 723–738 (2010)Cite this article

Abstract

Nuclear expression of CCAAT enhancer binding protein-α (C/EBPα), which supports tissue differentiation through several antiproliferative protein–protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBPα is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBPα acts as a corepressor of the classical androgen response element (ARE)-mediated gene activation by the androgen receptor (AR), but this is paradoxical as the genotropic actions of AR are crucial not only for the growth of the prostate but also for its maintenance and function. We show that DNA-bound C/EPBα recruits AR to activate transcription. C/EBPα-dependent trans-activation by AR also overrode suppression of AREs by C/EBPα elsewhere in a promoter. This mechanism was remarkable in that its androgen dependence was apparently for nuclear translocation of AR; it was otherwise androgen independent, flutamide insensitive and tolerant to disruption of AR dimerization. Gene response profiles and global chromatin associations in situ supported the direct bimodal regulation of AR transcriptional signaling by C/EBPα. This unique mechanism explains the functional coordination between AR and C/EPBα in the prostate and also shows that hormone-refractory AR signaling in prostate cancer could occur through receptor tethering.

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Acknowledgements

Supported by NIH R01 grants CA 103964 and CA 80183 to MR.

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Author notes

  1. J Zhang, M Gonit and M D Salazar: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, OH, USA

    J Zhang, M Gonit, M D Salazar, R Trumbly & M Ratnam

  2. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Trent Drive, Durham, NC, USA

    A Shatnawi

  3. Department of Biological Sciences, University of Toledo, W. Bancroft, Toledo, OH, USA

    L Shemshedini

  4. Bioinformatics and Proteomics/Genomics Core Division, Medical University of Ohio, Toledo, OH, USA

    R Trumbly

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Zhang, J., Gonit, M., Salazar, M. et al. C/EBPα redirects androgen receptor signaling through a unique bimodal interaction. Oncogene 29, 723–738 (2010). https://doi.org/10.1038/onc.2009.373

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