In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis

Vaidyanathan, Srividya, Cato, Kathleen, Tang, Lu, Pavey, Sandra, Haass, Nikolas K., Gabrielli, Brian G. and Duijf, Pascal H. G. (2016) In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis. Oncogene, . doi:10.1038/onc.2016.94


Author Vaidyanathan, Srividya
Cato, Kathleen
Tang, Lu
Pavey, Sandra
Haass, Nikolas K.
Gabrielli, Brian G.
Duijf, Pascal H. G.
Title In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis
Formatted title
In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis
Journal name Oncogene   Check publisher's open access policy
ISSN 1476-5594
0950-9232
Publication date 2016-04-11
Year available 2016
Sub-type Article (original research)
DOI 10.1038/onc.2016.94
Open Access Status Not Open Access
Total pages 10
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2017
Language eng
Formatted 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
Keyword EMI1
Chromosome instability
CIN
Tumorigenesis
Solid cancer
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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Created: Fri, 22 Apr 2016, 07:00:24 EST by Pascal Duijf on behalf of UQ Diamantina Institute