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MAGEA1 interacts with FBXW7 and regulates ubiquitin ligase-mediated turnover of NICD1 in breast and ovarian cancer cells

Oncogene volume 36, pages 5023–5034 (2017)Cite this article

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Abstract

Melanoma-associated antigen A1 (MAGEA1) is member of the MAGE gene family that is expressed in male germ line cells and placenta under normal physiological conditions. Although MAGEA1’s expression levels have been evaluated as one of the cancer testis (CT) antigens for immunotherapy in melanoma and several other cancers, its functional role and signaling mechanisms are largely unknown. In this study, we examined the functional involvement and signaling mechanisms of MAGEA1 in breast and ovarian cancer cells. Inhibitory effects of MAGEA1 on cell proliferation and migration were observed using both gain-of- (MAGEA1 overexpression) and loss-of- (siRNA interference) function approaches in breast (MCF-7 and MDA-MB-231) and ovarian (SKOV3 and SKOV3ip) cancer cell lines. We revealed a novel interaction between MAGEA1 and the intracellular segment of NOTCH1 receptor (NICD1). MAGEA1 reduced NICD1’s stability by promoting the ubiquitin modification of NICD1. MAGEA1 also interacted with FBXW7, subunit of E3 ubiquitin protein ligase complex SCF, and the latter was functionally involved in NICD1 ubiquitination and degradation. In addition, siRNA interference of FBXW7 reversed the inhibitory effect of MAGEA1 on migration and proliferation of MCF-7 and MDA-MB-231 cells. These newly discovered MAGEA1–NICD1 and MAGEA1–FBXW7 interactions have potential clinical implications in breast and ovarian cancer treatment.

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Acknowledgements

This work was supported in part by The National Basic Research Program of China (Grant no. 2007CB914401) and the National High Technology Research and Development Program of China (Grant no. 2006AA02Z4A6) to JS; as well as in part by the Mary Fendrich-Hulman Charitable Trust Fund to YX. We would like to thank Kevin McClelland for editing the manuscript.

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Authors and Affiliations

  1. Key Laboratory of Cell Proliferation and Regulation, College of Life Sciences, Beijing Normal University, Beijing, China

    J Zhao, Y Wang, C Mu & J Sang

  2. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA

    Y Xu

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Zhao, J., Wang, Y., Mu, C. et al. MAGEA1 interacts with FBXW7 and regulates ubiquitin ligase-mediated turnover of NICD1 in breast and ovarian cancer cells. Oncogene 36, 5023–5034 (2017). https://doi.org/10.1038/onc.2017.131

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