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Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen

Oncogene volume 33, pages 3441–3450 (2014)Cite this article

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Abstract

FKBPL has been implicated in processes associated with cancer, including regulation of tumor growth and angiogenesis with high levels of FKBPL prognosticating for improved patient survival. Understanding how FKBPL levels are controlled within the cell is therefore critical. We have identified a novel role for RBCK1 as an FKBPL-interacting protein, which regulates FKBPL stability at the post-translational level via ubiquitination. Both RBCK1 and FKBPL are upregulated by 17-β-estradiol and interact within heat shock protein 90 chaperone complexes, together with estrogen receptor-α (ERα). Furthermore, FKBPL and RBCK1 associate with ERα at the promoter of the estrogen responsive gene, pS2, and regulate pS2 levels. MCF-7 clones stably overexpressing RBCK1 were shown to have reduced proliferation and increased levels of FKBPL and p21. Furthermore, these clones were resistant to tamoxifen therapy, suggesting that RBCK1 could be a predictive marker of response to endocrine therapy. RBCK1 knockdown using targeted small interfering RNA resulted in increased proliferation and increased sensitivity to tamoxifen treatment. Moreover, in support of our in vitro data, analysis of mRNA microarray data sets demonstrated that high levels of FKBPL and RBCK1 correlated with increased patient survival, whereas high RBCK1 predicted for a poor response to tamoxifen. Our findings support a role for RBCK1 in the regulation of FKBPL with important implications for estrogen receptor signaling, cell proliferation and response to endocrine therapy.

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Acknowledgements

The financial support for this work was provided by PhD studentships awarded to C Donley and K McClelland from Department of Employment and Learning, Northern Ireland and Action Cancer, Northern Ireland, respectively. HD McKeen was supported by grants from Breast Cancer Campaign, United Kingdom and then the Medical Research Council, United Kingdom and A Yakkundi was supported by a grant from the Biotechnology and Biological Sciences Research Council, United Kingdom. All grants were awarded to T Robson.

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Author notes

  1. C Donley, K McClelland and H D McKeen: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, McClay Research Centre, Queen’s University, Belfast, Northern Ireland

    C Donley, K McClelland, H D McKeen, L Nelson, A Yakkundi, J Burrows, L McClements, A Valentine, H O McCarthy & T Robson

  2. Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, UK

    P V Jithesh

  3. Centre for Cancer Research and Cell Biology, Queen’s University, Belfast, Northern Ireland

    K M Prise

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  1. C Donley
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Correspondence to T Robson.

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Donley, C., McClelland, K., McKeen, H. et al. Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen. Oncogene 33, 3441–3450 (2014). https://doi.org/10.1038/onc.2013.306

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