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TRPS1 regulates oestrogen receptor binding and histone acetylation at enhancers

Oncogene volume 37, pages 5281–5291 (2018)Cite this article

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Abstract

The chromatin state is finely tuned to regulate function and specificity for transcription factors such as oestrogen receptor alpha (ER), which contributes to cell growth in breast cancer. ER transcriptional potential is mediated, in large part, by the specific associated proteins and co-factors that interact with it. Despite the identification and characterisation of several ER coregulators, a complete and systematic view of ER-regulating chromatin modifiers is lacking. By exploiting a focused siRNA screen that investigated the requirement for a library of 330 chromatin regulators in ER-mediated cell growth, we find that the NuRD and coREST histone deacetylation complexes are critical for breast cancer cell proliferation. Further, by proteomic and genomics approaches, we discover the transcription factor TRPS1 to be a key interactor of the NuRD and coREST complexes. Interestingly, TRPS1 gene amplification occurs in 28% of human breast tumours and is associated with poor prognosis. We propose that TRPS1 is required to repress spurious binding of ER, where it contributes to the removal of histone acetylation. Our data suggest that TRPS1 is an important ER-associated transcriptional repressor that regulates cell proliferation, chromatin acetylation and ER binding at the chromatin of cis-regulatory elements.

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Acknowledgements

We would like to thank Clive D’Santos and Chris Taylor from the CRUK CI Proteomics core, James Hadfield and the other members of the Genomics core, and Suraj Menon from the Bioinformatics core. Jason Carroll is supported by an ERC Consolidator grant and a Komen Scholar Award. We would like to acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.

Author contributions

AAS, HM, KWM and JSC designed the project and wrote the manuscript. AAS, HM and AM performed the experiments and analysed the data.

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Authors and Affiliations

  1. Cambridge Institute, Cancer Research UK, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK

    A. A. Serandour, H. Mohammed, A. Miremadi, K. W. Mulder & J. S. Carroll

  2. CRCINA, INSERM, CNRS, Université d’Angers, Université de Nantes; Ecole Centrale de Nantes, Nantes, France

    A. A. Serandour

  3. Knight Cancer Early Detection Advanced Research Center, Oregon Health and Science University, Portland, Oregon, USA

    H. Mohammed

  4. Faculty of Science, Radboud Institute for Molecular Life Sciences, Department of Molecular Developmental Biology, Radboud University, Nijmegen, The Netherlands

    K. W. Mulder

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These authors contributed equally: A.A. Serandour and H. Mohammed.

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Serandour, A.A., Mohammed, H., Miremadi, A. et al. TRPS1 regulates oestrogen receptor binding and histone acetylation at enhancers. Oncogene 37, 5281–5291 (2018). https://doi.org/10.1038/s41388-018-0312-2

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