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Cellular stress induces TRB3/USP9x-dependent Notch activation in cancer

Oncogene volume 36, pages 1048–1057 (2017)Cite this article

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Abstract

Expression of the Notch ligand JAG1 and Notch pathway activation promote poor prognosis, basal-like breast cancer. We have recently shown that the pseudokinase Tribbles homolog 3 (TRB3) regulates JAG1 expression in this malignancy. TRB3 is a stress and metabolic sensor, and here we show that nutrient deprivation or endoplasmic reticulum stress markedly upregulate TRB3, which serves as a scaffold for the deubiquitinase USP9x. USP9x in turn stimulates JAG1 activity through two mechanisms: (1) through TRB3 deubiquitination and stabilization, and (2) through deubiquitination and activation of Mind Bomb 1, an E3 ligase required for JAG1 ubiquitination-mediated endocytosis and Notch activation. These USP9x activities are confined to the signal-sending cell of a cell pair undergoing Notch signaling. We demonstrate that USP9x is required for TRB3 upregulation and Notch activation in response to cellular stress in basal-like breast cancer cells. These data suggest that TRB3 functions as a sensor of tumor microenvironmental stress and together with USP9x induces the cell survival and tumor-promoting activities of Notch. These findings identify a novel mechanism by which cancer cells survive in their hostile environment and provide potential therapeutic _targets in breast cancer.

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Acknowledgements

This study was supported by funds to MR from the Canadian Breast Cancer Foundation. This research was funded in part by the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the OMOHLTC. We thank J Tong for technical support, and B Martin and P Taylor for bioinformatic support.

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Authors and Affiliations

  1. Campbell Family Institute for Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada

    J Izrailit, A Jaiswal, W Zheng & M Reedijk

  2. Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada

    J Izrailit, A Jaiswal & M Reedijk

  3. Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, ON, Canada

    M F Moran

  4. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    M F Moran

  5. Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    M Reedijk

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Correspondence to M Reedijk.

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Izrailit, J., Jaiswal, A., Zheng, W. et al. Cellular stress induces TRB3/USP9x-dependent Notch activation in cancer. Oncogene 36, 1048–1057 (2017). https://doi.org/10.1038/onc.2016.276

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