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Article: Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance

TitlePaclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel 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. 8, p. 990-1002 How to Cite?
AbstractFOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated beta-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7TaxR cells. KIF20A depletion also renders MCF-7 and MCF-7TaxR cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance.Oncogene advance online publication, 11 May 2015; doi:10.1038/onc.2015.152.
Persistent Identifierhttp://hdl.handle.net/10722/215258
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047

 

DC FieldValueLanguage
dc.contributor.authorKhongkow, P-
dc.contributor.authorGomes, AR-
dc.contributor.authorGong, C-
dc.contributor.authorMan, PS-
dc.contributor.authorTsang, JWH-
dc.contributor.authorZhao, F-
dc.contributor.authorMonteiro, LJ-
dc.contributor.authorCoombes, RC-
dc.contributor.authorMedema, RH-
dc.contributor.authorKhoo, US-
dc.contributor.authorLam, EW-
dc.date.accessioned2015-08-21T13:19:32Z-
dc.date.available2015-08-21T13:19:32Z-
dc.date.issued2015-
dc.identifier.citationOncogene, 2015, v. 35 n. 8, p. 990-1002-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/215258-
dc.description.abstractFOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated beta-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7TaxR cells. KIF20A depletion also renders MCF-7 and MCF-7TaxR cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance.Oncogene advance online publication, 11 May 2015; doi:10.1038/onc.2015.152.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titlePaclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance-
dc.typeArticle-
dc.identifier.emailMan, PS: ellenman@hku.hk-
dc.identifier.emailTsang, JWH: jwhtsang@hku.hk-
dc.identifier.emailZhao, F: zhaofung@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.2015.152-
dc.identifier.hkuros249218-
dc.identifier.volume35-
dc.identifier.issue8-
dc.identifier.spage990-
dc.identifier.epage1002-
dc.publisher.placeUnited Kingdom-

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