Myatt, Stephen S., Kongsema, M., Man, Cornelia W-Y., Kelly, D. J., Gomes, Ana R., Khongkow, P., Karunarathna, U., Zona, Stefania, Langer, J. K., Dunsby, C. W., Coombes, R. C., French, P. M., Brosens, Jan J. and Lam, Eric W.-F. (2014) SUMOylation inhibits FOXM1 activity and delays mitotic transition. Oncogene, Volume 33 (Number 34). pp. 4316-4329. doi:10.1038/onc.2013.546 ISSN 0950-9232.

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Abstract

The forkhead box transcription factor FOXM1 is an essential effector of G2/M-phase transition, mitosis and the DNA damage response. As such, it is frequently deregulated during tumorigenesis. Here we report that FOXM1 is dynamically modified by SUMO1 but not by SUMO2/3 at multiple sites. We show that FOXM1 SUMOylation is enhanced in MCF-7 breast cancer cells in response to treatment with epirubicin and mitotic inhibitors. Mutation of five consensus conjugation motifs yielded a SUMOylation-deficient mutant FOXM1. Conversely, fusion of the E2 ligase Ubc9 to FOXM1 generated an auto-SUMOylating mutant (FOXM1-Ubc9). Analysis of wild-type FOXM1 and mutants revealed that SUMOylation inhibits FOXM1 activity, promotes translocation to the cytoplasm and enhances APC/Cdh1-mediated ubiquitination and degradation. Further, expression of the SUMOylation-deficient mutant enhanced cell proliferation compared with wild-type FOXM1, whereas the FOXM1-Ubc9 fusion protein resulted in persistent cyclin B1 expression and slowed the time from mitotic entry to exit. In summary, our findings suggest that SUMOylation attenuates FOXM1 activity and causes mitotic delay in cytotoxic drug response.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Chemotherapy, Drug resistance in cancer cells, Breast -- Cancer, Cell cycle
Journal or Publication Title:	Oncogene
Publisher:	Nature Publishing Group
ISSN:	0950-9232
Official Date:	23 December 2014
Dates:	Date Event 23 December 2014 Available 18 November 2013 Accepted 18 April 2013 Submitted
Volume:	Volume 33
Number:	Number 34
Page Range:	pp. 4316-4329
DOI:	10.1038/onc.2013.546
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	28 December 2015
Date of first compliant Open Access:	28 December 2015
Funder:	Breast Cancer Campaign, Cancer Research UK (CRUK), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Engineering and Physical Sciences Research Council (EPSRC), University Hospitals Coventry and Warwickshire NHS Trust
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