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Tumor suppressor bromodomain-containing protein 7 cooperates with Smads to promote transforming growth factor-β responses

Oncogene volume 36, pages 362–372 (2017)Cite this article

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Abstract

Smad proteins are central mediators in the canonical transforming growth factor-β (TGF-β) signaling pathway in mammalian cells. We report here that bromodomain-containing protein 7 (BRD7) functions as a novel transcription coactivator for Smads in TGF-β signaling. BRD7 forms a TGF-β inducible complex with Smad3/4 through its N-terminal Smad-binding domain. BRD7 simultaneously binds to acetylated histones to promote Smad-chromatin association, and associates with histone acetyltransferase p300 to enhance Smad transcriptional activity. Ectopic expression of BRD7, but not its mutants defective in Smad binding, enhances TGF-β transcriptional, tumor-suppressing and epithelial-mesenchymal transition responses. Conversely, depletion of BRD7 inhibits TGF-β responses. Thus, our study provides compelling evidence for a new function of BRD7 in fine-tuning TGF-β physiological responses.

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Abbreviations

acH3K9:

acetyl histone H3 Lys9

BMP:

bone morphogenetic protein

BRD7:

bromodomain-containing protein 7

EMT:

epithelial-mesenchymal transition

GST:

glutathione S-transferase

HAT:

histone acetyltransferase

P/CAF:

p300/CBP-associated factor

qRT-PCR:

quantitative real-time PCR

SIP1:

Smad-interacting protein 1

TGF:

transforming growth factor beta

TGIF:

TG-interacting factor

SMIF:

Smad4-interacting protein

SXS motif:

Ser-X-Ser motif

WT:

wild-type.

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Acknowledgements

We thank David Luskutoff for p800 (PAI-1)-luc, Bert Vogelstein for WWP1 (p21)-luc and SBE-luc. We are grateful to the laboratory members for helpful discussion and technical assistance. This research was partly supported by grants from NSFC (91540205, 31571447, 31171347) and MOST (2012CB966600, 2015CB553800, 2013CB945303), NIH (R01GM63773, R01AR053591, R01CA108454, and R01DK073932), Project 111, PhD Programs Foundation of Ministry of Education of China (20110101120152), and the Fundamental Research Funds for the Central Universities.

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Author notes

  1. T Liu and M Zhao: These authors contributed equally to this work.

Authors and Affiliations

  1. Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Zhejiang, China

    T Liu, M Zhao, J Liu, Z He, Y Zhang, J Huang & X-H Feng

  2. Department of Cell Biology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Zhejiang, China

    T Liu

  3. State Key Laboratory of Cellular Stress Biology and Innovation Center for Cell Signaling Network, College of Life Sciences, Fujian, China

    H You

  4. Michael E. DeBakey Department of Surgery and Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    X Lin & X-H Feng

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Correspondence to T Liu or X-H Feng.

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Liu, T., Zhao, M., Liu, J. et al. Tumor suppressor bromodomain-containing protein 7 cooperates with Smads to promote transforming growth factor-β responses. Oncogene 36, 362–372 (2017). https://doi.org/10.1038/onc.2016.204

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