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RNF168 cooperates with RNF8 to mediate FOXM1 ubiquitination and degradation in breast cancer epirubicin treatment

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Title: RNF168 cooperates with RNF8 to mediate FOXM1 ubiquitination and degradation in breast cancer epirubicin treatment
Authors: Lam, EW
Kongsema, M
Zona, S
Karunarathna, U
Yao, S
Item Type: Journal Article
Abstract: The forkhead box M1 (FOXM1) transcription factor has a central role in genotoxic agent response in breast cancer. FOXM1 is regulated at the post-translational level upon DNA damage, but the key mechanism involved remained enigmatic. RNF168 is a ubiquitination E3-ligase involved in DNA damage response. Western blot and gene promoter-reporter analyses showed that the expression level and transcriptional activity of FOXM1 reduced upon RNF168 overexpression and increased with RNF168 depletion by siRNA, suggesting that RNF168 negatively regulates FOXM1 expression. Co-immunoprecipitation studies in MCF-7 cells revealed that RNF168 interacted with FOXM1 and that upon epirubicin treatment FOXM1 downregulation was associated with an increase in RNF168 binding and conjugation to the protein degradation-associated K48-linked polyubiquitin chains. Consistently, RNF168 overexpression resulted in an increase in turnover of FOXM1 in MCF-7 cells treated with the protein synthesis inhibitor cycloheximide. Conversely, RNF168, knockdown significantly enhanced the half-life of FOXM1 in both absence and presence of epirubicin. Using a SUMOylation-defective FOXM1-5x(K>R) mutant, we demonstrated that SUMOylation is required for the recruitment of RNF168 to mediate FOXM1 degradation. In addition, clonogenic assays also showed that RNF168 mediates epirubicin action through targeting FOXM1, as RNF168 could synergise with epirubicin to repress clonal formation in wild-type but not in FOXM1-deficient mouse embryo fibroblasts (MEFs). The physiological relevance of RNF168-mediated FOXM1 repression is further emphasized by the significant inverse correlation between FOXM1 and RNF168 expression in breast cancer patient samples. Moreover, we also obtained evidence that RNF8 recruits RNF168 to FOXM1 upon epirubicin treatment and cooperates with RNF168 to catalyse FOXM1 ubiquitination and degradation. Collectively, these data suggest that RNF168 cooperates with RNF8 to mediate the ubiquitination and degradation of SUMOylated FOXM1 in breast cancer genotoxic response.
Issue Date: 15-Aug-2016
Date of Acceptance: 30-Jun-2016
URI: http://hdl.handle.net/10044/1/34302
DOI: http://dx.doi.org/10.1038/oncsis.2016.57
ISSN: 2157-9024
Publisher: Nature Publishing Group
Journal / Book Title: Oncogenesis
Volume: 5
Copyright Statement: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Campaign and Breakthrough Breast Cancer
Imperial College Trust
Funder's Grant Number: C37/A12011
2012NovemberPhD016
2012MayPR070
N/A
Publication Status: Published
Article Number: e252
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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