title: SUMOylation inhibits FOXM1 activity and delays mitotic transition.
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.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: S S
authors.initials: SS
authors.lastname: Myatt
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Kongsema
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR China.
authors.forename: C W-Y
authors.initials: CW
authors.lastname: Man
authors.affiliation: 1] Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK [2] Photonics Group, Department of Physics, Imperial College London, London, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Gomes
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Khongkow
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: U
authors.initials: U
authors.lastname: Karunarathna
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Zona
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Langer
authors.affiliation: Photonics Group, Department of Physics, Imperial College London, London, UK.
authors.forename: C W
authors.initials: CW
authors.lastname: Dunsby
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Photonics Group, Department of Physics, Imperial College London, London, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: French
authors.affiliation: Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry, UK.
authors.forename: J J
authors.initials: JJ
authors.lastname: Brosens
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK.
authors.forename: E W-F
authors.initials: EW
authors.lastname: Lam
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015703:Antigens, CD; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000494:pharmacology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008938:Mitosis; D015739:Nocodazole / Q000494:pharmacology; D021381:Protein Transport; D059748:Proteolysis; D025842:SUMO-1 Protein / Q000378:metabolism*; D058207:Sumoylation
chemical_list: D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D015251:Epirubicin; D015739:Nocodazole