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Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4

Oncogene volume 36, pages 5177–5188 (2017)Cite this article

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Abstract

BRD4 has emerged as an important factor in tumorigenesis by promoting the transcription of genes involved in cancer development. However, how BRD4 is regulated in cancer cells remains largely unknown. Here, we report that the stability and functions of BRD4 are positively regulated by prolyl isomerase PIN1 in gastric cancer cells. PIN1 directly binds to phosphorylated threonine (T) 204 of BRD4 as revealed by peptide binding and crystallographic studies and enhances BRD4’s stability by inhibiting its ubiquitination. PIN1 also catalyses the isomerization of proline 205 of BRD4 and induces its conformational change, which promotes its interaction with CDK9 and increases BRD4’s transcriptional activity. Substitution of BRD4 with PIN1-binding-defective BRD4-T204A mutant in gastric cancer cells reduces BRD4’s stability, attenuates BRD4-mediated gene expression by impairing its interaction with CDK9 and suppresses gastric cancer cell proliferation, migration and invasion, and tumor formation. Our results identify BRD4 as a new target of PIN1 and suggest that interfering with their interaction could be a potential therapeutic approach for cancer treatment.

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Acknowledgements

We thank members in the Chen lab for discussion. This work is supported in part by fund provided by UIUC (to LFC) and NIH grants DK085158 and CA179511 (to LFC) and Natural Science Foundation of China Grants 81361120386 (to RC).

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Authors and Affiliations

  1. Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    X Hu, S-H Dong, J Chen, S Nair & L-F Chen

  2. Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA

    X Z Zhou & K P Lu

  3. The State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China

    R Chen

  4. Institute for Translational Medicine, Fujian Medical University, Fuzhou, China

    K P Lu

  5. Department of Medical Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    L-F Chen

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Correspondence to L-F Chen.

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Competing interests

Dr Lu and Dr Zhou are inventors of Pin1 technology, which was licensed by BIDMC to Pinteon Therapeutics. Both Dr Lu and Dr Zhou own equity in, and consult for Pinteon. Their interests were reviewed and are managed by BIDMC in accordance with its conflict of interest policy.

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Hu, X., Dong, SH., Chen, J. et al. Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4. Oncogene 36, 5177–5188 (2017). https://doi.org/10.1038/onc.2017.137

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