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Article: OTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance

TitleOTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance
Authors
Issue Date2015
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2015, v. 35 n. 11, p. 1433-1444 How to Cite?
AbstractThe forkhead transcription factor FOXM1 has a key role in DNA damage response, and its deregulated overexpression is associated with genotoxic drug resistance in breast cancer. However, little is known about the posttranslational mechanisms by which FOXM1 expression is regulated by genotoxic agents and how they are deregulated in resistant cells. Initial co-immunoprecipitation studies verified previous proteomic analysis finding that the OTUB1 is a novel FOXM1-interacting protein. Western blot analysis showed that both OTUB1 and FOXM1 expression reduced upon genotoxic agent treatment in MCF-7 cells, but remained relatively constant in resistant cells. FOXM1 expression reduced upon OTUB1 depletion by siRNA and increased with OTUB1 overexpression in MCF-7 cells, arguing that OTUB1 positively regulates FOXM1 expression. In agreement, co-immunoprecipitation experiments demonstrated that FOXM1 expression is associated with OTUB1 binding but inversely correlates with conjugation to the protein degradation-associated Lys-48-linked ubiquitin-chains. Overexpression of wild-type (WT) OTUB1, but not the OTUB1(C91S) mutant, disrupted the formation of Lys48-linked ubiquitin-conjugates on FOXM1. Importantly, knockdown of OTUB1 by siRNA resulted in an increase in turnover of FOXM1 in MCF-7 cells treated with the protein synthesis inhibitor cycloheximide, whereas overexpression of WT OTUB1, but not the OTUB1(C91S) mutant, significantly enhances the half-life of FOXM1. In addition, proliferative and clonogenic assays also show that OTUB1 can enhance the proliferative rate and epirubicin resistance through targeting FOXM1, as OTUB1 has little effect on FOXM1-deficient cells. The physiological relevance of the regulation of FOXM1 by OTUB1 is further underscored by the significant correlations between FOXM1 and OTUB1 expression in breast cancer patient samples. Cox-regression survival analysis indicates that OTUB1 overexpression is linked to poorer outcome in particular in patients treated with chemotherapy. Collectively, these data suggest that OTUB1 limits the ubiquitination and degradation of FOXM1 in breast cancer and has a key role in genotoxic agent resistance.Oncogene advance online publication, 6 July 2015; doi:10.1038/onc.2015.208.
Persistent Identifierhttp://hdl.handle.net/10722/215259
ISSN
2023 Impact Factor: 6.9
2023 SCImago Journal Rankings: 2.334
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKarunarathna, U-
dc.contributor.authorKongsema, M-
dc.contributor.authorZona, S-
dc.contributor.authorGong, C-
dc.contributor.authorCabrera, E-
dc.contributor.authorGomes, AR-
dc.contributor.authorMan, PS-
dc.contributor.authorKhongkow, P-
dc.contributor.authorTsang, JWH-
dc.contributor.authorKhoo, US-
dc.contributor.authorMedema, RH-
dc.contributor.authorFreire, R-
dc.contributor.authorLam, EW-
dc.date.accessioned2015-08-21T13:19:34Z-
dc.date.available2015-08-21T13:19:34Z-
dc.date.issued2015-
dc.identifier.citationOncogene, 2015, v. 35 n. 11, p. 1433-1444-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/215259-
dc.description.abstractThe forkhead transcription factor FOXM1 has a key role in DNA damage response, and its deregulated overexpression is associated with genotoxic drug resistance in breast cancer. However, little is known about the posttranslational mechanisms by which FOXM1 expression is regulated by genotoxic agents and how they are deregulated in resistant cells. Initial co-immunoprecipitation studies verified previous proteomic analysis finding that the OTUB1 is a novel FOXM1-interacting protein. Western blot analysis showed that both OTUB1 and FOXM1 expression reduced upon genotoxic agent treatment in MCF-7 cells, but remained relatively constant in resistant cells. FOXM1 expression reduced upon OTUB1 depletion by siRNA and increased with OTUB1 overexpression in MCF-7 cells, arguing that OTUB1 positively regulates FOXM1 expression. In agreement, co-immunoprecipitation experiments demonstrated that FOXM1 expression is associated with OTUB1 binding but inversely correlates with conjugation to the protein degradation-associated Lys-48-linked ubiquitin-chains. Overexpression of wild-type (WT) OTUB1, but not the OTUB1(C91S) mutant, disrupted the formation of Lys48-linked ubiquitin-conjugates on FOXM1. Importantly, knockdown of OTUB1 by siRNA resulted in an increase in turnover of FOXM1 in MCF-7 cells treated with the protein synthesis inhibitor cycloheximide, whereas overexpression of WT OTUB1, but not the OTUB1(C91S) mutant, significantly enhances the half-life of FOXM1. In addition, proliferative and clonogenic assays also show that OTUB1 can enhance the proliferative rate and epirubicin resistance through targeting FOXM1, as OTUB1 has little effect on FOXM1-deficient cells. The physiological relevance of the regulation of FOXM1 by OTUB1 is further underscored by the significant correlations between FOXM1 and OTUB1 expression in breast cancer patient samples. Cox-regression survival analysis indicates that OTUB1 overexpression is linked to poorer outcome in particular in patients treated with chemotherapy. Collectively, these data suggest that OTUB1 limits the ubiquitination and degradation of FOXM1 in breast cancer and has a key role in genotoxic agent resistance.Oncogene advance online publication, 6 July 2015; doi:10.1038/onc.2015.208.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleOTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance-
dc.typeArticle-
dc.identifier.emailMan, PS: ellenman@hku.hk-
dc.identifier.emailTsang, JWH: jwhtsang@hku.hk-
dc.identifier.emailKhoo, US: uskhoo@hku.hk-
dc.identifier.authorityTsang, JWH=rp00278-
dc.identifier.authorityKhoo, US=rp00362-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/onc.2015.208-
dc.identifier.scopuseid_2-s2.0-84935492499-
dc.identifier.hkuros249219-
dc.identifier.volume35-
dc.identifier.issue11-
dc.identifier.spage1433-
dc.identifier.epage1444-
dc.identifier.isiWOS:000372196400009-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl0950-9232-

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