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Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2

Oncogene volume 33, pages 3235–3245 (2014)Cite this article

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Abstract

The androgen receptor (AR) is a transcription factor that employs many diverse interactions with coregulatory proteins in normal physiology and in prostate cancer (PCa). The AR mediates cellular responses in association with chromatin complexes and kinase cascades. Here we report that the nuclear matrix protein, scaffold attachment factor B1 (SAFB1), regulates AR activity and AR levels in a manner that suggests its involvement in PCa. SAFB1 mRNA expression was lower in PCa in comparison with normal prostate tissue in a majority of publicly available RNA expression data sets. SAFB1 protein levels were also reduced with disease progression in a cohort of human PCa that included metastatic tumors. SAFB1 bound to AR and was phosphorylated by the MST1 (Hippo homolog) serine-threonine kinase, previously shown to be an AR repressor, and MST1 localization to AR-dependent promoters was inhibited by SAFB1 depletion. Knockdown of SAFB1 in androgen-dependent LNCaP PCa cells increased AR and prostate-specific antigen (PSA) levels, stimulated growth of cultured cells and subcutaneous xenografts and promoted a more aggressive phenotype, consistent with a repressive AR regulatory function. SAFB1 formed a complex with the histone methyltransferase EZH2 at AR-interacting chromatin sites in association with other polycomb repressive complex 2 (PRC2) proteins. We conclude that SAFB1 acts as a novel AR co-regulator at gene loci where signals from the MST1/Hippo and EZH2 pathways converge.

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Acknowledgements

We thank Thomas Roberts (Dana-Farber Cancer Institute) for critical comments and Delia Lopez, Kristine Pelton and Paul Guthrie for technical assistance. This study was supported by NIH 1R01CA143777, 1R01CA112303, and US Department of Defense PC093459 (to MRF), NIH 5R00CA131472 (to DDV) and NIH R01 CA097213 (to SO).

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Authors and Affiliations

  1. Departments of Surgery, Cancer Biology Program, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    N K Mukhopadhyay, J Kim, S You, M Morello, W-C Huang, J Yang, B Cinar, D Di Vizio & M R Freeman

  2. Department of Surgery, Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA

    J Kim, M H Hager, A Ramachandran, R M Adam, D Di Vizio & M R Freeman

  3. Department of Pathology and Laboratory Medicine, Weill Cornell Medical Centre, New York, NY, USA

    M A Rubin

  4. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    S Oesterreich

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Correspondence to M R Freeman.

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Mukhopadhyay, N., Kim, J., You, S. et al. Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2. Oncogene 33, 3235–3245 (2014). https://doi.org/10.1038/onc.2013.294

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