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Glucose-regulated protein 78 as a novel effector of BRCA1 for inhibiting stress-induced apoptosis

Oncogene volume 27, pages 6782–6789 (2008)Cite this article

Abstract

The tumor suppressor BRCA1 is mutated in a high percentage of familial breast and ovarian cancer, but our understanding of its mechanisms of action remains incomplete. We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression. Knockdown of BRCA1 also led to induction of other components of UPR, such as GRP94 and CHOP. Consistent with a role of BRCA1 knockdown in mediating cell survival, forced expression of GRP78 stimulated cell proliferation and prevented apoptosis, including that induced by endoplasmic reticulum stress and chemotherapy, in ovarian OVCAR-3 and breast MCF-7 cancer cells. Overexpression of wild-type BRCA1 could increase the apoptosis of GRP78-overexpressing cells. Conversely, knockdown GRP78 by siRNA sensitized ovarian and breast cancer cells to apoptosis. This effect was reduced when the expression of BRCA1 was simultaneously knockdown by siRNA, indicating that BRCA1 also negatively regulates GRP78-mediated cell survival and resistance to apoptosis.

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Acknowledgements

The present work was supported by Hong Kong Research Grants Council Grant (7484/04M) (AST Wong).

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Author notes

  1. B H Y Yeung and B W Y Kwan: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Biological Sciences, University of Hong Kong, Hong Kong, China

    B H Y Yeung, B W Y Kwan & A S T Wong

  2. Institute of Life and Health Engineering, Jinan University, Guangzhou, China

    Q Y He

  3. Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    A S Lee

  4. Department of Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA

    J Liu

Authors
  1. B H Y Yeung
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  2. B W Y Kwan
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  3. Q Y He
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  4. A S Lee
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  5. J Liu
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  6. A S T Wong
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Corresponding author

Correspondence to A S T Wong.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Yeung, B., Kwan, B., He, Q. et al. Glucose-regulated protein 78 as a novel effector of BRCA1 for inhibiting stress-induced apoptosis. Oncogene 27, 6782–6789 (2008). https://doi.org/10.1038/onc.2008.290

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