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In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis

Oncogene volume 35, pages 5446–5455 (2016)Cite this article

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Abstract

Cell cycle genes are often aberrantly expressed in cancer, but how their misexpression drives tumorigenesis mostly remains unclear. From S phase to early mitosis, EMI1 (also known as FBXO5) inhibits the anaphase-promoting complex/cyclosome, which controls cell cycle progression through the sequential degradation of various substrates. By analyzing 7403 human tumor samples, we find that EMI1 overexpression is widespread in solid tumors but not in blood cancers. In solid cancers, EMI1 overexpression is a strong prognostic marker for poor patient outcome. To investigate causality, we generated a transgenic mouse model in which we overexpressed Emi1. Emi1-overexpressing animals develop a wide variety of solid tumors, in particular adenomas and carcinomas with inflammation and lymphocyte infiltration, but not blood cancers. These tumors are significantly larger and more penetrant, abundant, proliferative and metastatic than control tumors. In addition, they are highly aneuploid with tumor cells frequently being in early mitosis and showing mitotic abnormalities, including lagging and incorrectly segregating chromosomes. We further demonstrate in vitro that even though EMI1 overexpression may cause mitotic arrest and cell death, it also promotes chromosome instability (CIN) following delayed chromosome alignment and anaphase onset. In human solid tumors, EMI1 is co-expressed with many markers for CIN and EMI1 overexpression is a stronger marker for CIN than most well-established ones. The fact that Emi1 overexpression promotes CIN and the formation of solid cancers in vivo indicates that Emi1 overexpression actively drives solid tumorigenesis. These novel mechanistic insights have important clinical implications.

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Acknowledgements

We thank Robert Benezra for support, Kym French for animal husbandry, Andrew Brooks for plasmids, Sandrine Roy, Ali Ju, Loredana Spoerri, Yvette Chin and Nicole Chee for technical assistance, Kim-Anh Lê Cao for statistical advice, Marianna Datseris for general support and Pulari Thangavelu and Mehlika Hazar-Rethinam for critically reading the manuscript. This work was supported by IPRS and University of Queensland (UQ) Centennial Scholarships (to SV), grants from UQ Diamantina Institute and UQ and a Career Development Fellowship from the National Breast Cancer Foundation (to PHGD).

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  1. S Vaidyanathan and K Cato: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia

    S Vaidyanathan, K Cato, L Tang, S Pavey, N K Haass, B G Gabrielli & P H G Duijf

  2. School of Basic Medical Sciences, Fudan University, Shanghai, China

    L Tang

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  1. S Vaidyanathan
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Correspondence to P H G Duijf.

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Vaidyanathan, S., Cato, K., Tang, L. et al. In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis. Oncogene 35, 5446–5455 (2016). https://doi.org/10.1038/onc.2016.94

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