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Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Oncogene volume 38, pages 5725–5738 (2019)Cite this article

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Abstract

Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor growth. Here we report the identification of 118 proteins interacting with endogenous chromatin-bound Fra-1 in TNBC cells, highlighting DDX5 as the most enriched Fra-1-interacting protein. DDX5, a previously unrecognized protein in the Fra-1 transcriptional network, shows extensive overlap with Fra-1 cistrome and transcriptome that are highly associated with the TNBC cell growth. We provide evidence that DDX5 expression enhances Fra-1 transcriptional activity and potentiates Fra-1-driven cell proliferation. Furthermore, we show that the DDX5 target gene signature predicts poor clinical outcome in breast cancer patients. DDX5 protein level was higher in triple-negative basal-like tumors than in non-basal-like tumors, including luminal A, luminal B, and HER2-enriched subtypes. Collectively, by combining proteomic and genomic approaches we reveal a role for DDX5 as a regulatory protein of Fra-1 signaling and suggest DDX5 as a potential therapeutic target for TNBC.

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Acknowledgements

This work was supported by scholarship from the China Scholarship Council, a Ph.D. student grant (KID) from the Karolinska Institutet and grants from the Swedish Cancer Society (Cancerfonden) and the Swedish Research Council. We thank SciLifeLab, Stockholm, for their RNA-seq technical support and the Karolinska Institute/Astra Zeneca Integrated Cardio Metabolic Center (ICMC) for their consultative support. We are grateful to Karin Dahlman-Wright for critically reading the first version of the manuscript.

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Authors and Affiliations

  1. Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83, Huddinge, Sweden

    Huan He, Dandan Song, Indranil Sinha, Lars-Arne Haldosen & Chunyan Zhao

  2. Center for Molecular Biology (ZMBH), University of Heidelberg, 69120, Heidelberg, Germany

    Bernd Hessling

  3. German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Bernd Hessling

  4. Integrated Cardio Metabolic Centre (ICMC), Department of Medicine, Karolinska Institutet, S-141 83, Huddinge, Sweden

    Xidan Li

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  1. Huan He
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Contributions

HH and DS performed experiments; IS, XL, HH, BH, and CZ analyzed data; HH and CZ interpreted results of experiments; HH, DS, and CZ prepared figures; HH and CZ drafted the manuscript; HH, L-AH, and CZ edited and revised the manuscript; all authors approved the final version of manuscript; CZ initiated and designed the study and supervised HH and DS.

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Correspondence to Chunyan Zhao.

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He, H., Song, D., Sinha, I. et al. Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1. Oncogene 38, 5725–5738 (2019). https://doi.org/10.1038/s41388-019-0824-4

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