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Article: FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer
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TitleFOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer
 
AuthorsKaradedou, CT3
Gomes, AR3
Chen, J3 2
Petkovic, M3
Ho, KK3
Zwolinska, AK3
Feltes, A3
Wong, SY2
Chan, KYK2
Cheung, YN2
Tsang, JWH1
Brosens, JJ3
Khoo, US2
Lam, EWF3
 
Issue Date2012
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
CitationOncogene, 2012, v. 31 n. 14, p. 1845-1858 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2011.368
 
AbstractVascular endothelial growth factor (VEGF) has a central role in breast cancer development and progression, but the mechanisms that control its expression are poorly understood. Breast cancer tissue microarrays revealed an inverse correlation between the Forkhead transcription factor Forkhead box class O (FOXO)3a and VEGF expression. Using the lapatinib-sensitive breast cancer cell lines BT474 and SKBR3 as model systems, we tested the possibility that VEGF expression is negatively regulated by FOXO3a. Lapatinib treatment of BT474 or SKBR3 cells resulted in nuclear translocation and activation of FOXO3a, followed by a reduction in VEGF expression. Transient transfection and inducible expression experiments showed that FOXO3a represses the proximal VEGF promoter, whereas another Forkhead member, FOXM1, induces VEGF expression. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that both FOXO3a and FOXM1 bind a consensus Forkhead response element (FHRE) in the VEGF promoter. Upon lapatinib stimulation, activated FOXO3a displaces FOXM1 bound to the FHRE before recruiting histone deacetylase 2 (HDAC2) to the promoter, leading to decreased histones H3 and H4 acetylation, and concomitant transcriptional inhibition of VEGF. These results show that FOXO3a-dependent repression of target genes in breast cancer cells, such as VEGF, involves competitive displacement of DNA-bound FOXM1 and active recruitment of transcriptional repressor complexes.
 
ISSN0950-9232
2012 Impact Factor: 7.357
2012 SCImago Journal Rankings: 3.558
 
DOIhttp://dx.doi.org/10.1038/onc.2011.368
 
PubMed Central IDPMC3232453
 
ISI Accession Number IDWOS:000302785200010
Funding AgencyGrant Number
Cancer Research UK
Breast Cancer Campaign
Portuguese Science and Technology Foundation (FCT)
Funding Information:

This study was supported by the Cancer Research UK (M Petkovic, KK Ho and EW-F Lam), Breast Cancer Campaign (EW-F Lam), the Portuguese Science and Technology Foundation (FCT; AR Gomes).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorKaradedou, CT
 
dc.contributor.authorGomes, AR
 
dc.contributor.authorChen, J
 
dc.contributor.authorPetkovic, M
 
dc.contributor.authorHo, KK
 
dc.contributor.authorZwolinska, AK
 
dc.contributor.authorFeltes, A
 
dc.contributor.authorWong, SY
 
dc.contributor.authorChan, KYK
 
dc.contributor.authorCheung, YN
 
dc.contributor.authorTsang, JWH
 
dc.contributor.authorBrosens, JJ
 
dc.contributor.authorKhoo, US
 
dc.contributor.authorLam, EWF
 
dc.date.accessioned2012-05-29T06:14:43Z
 
dc.date.available2012-05-29T06:14:43Z
 
dc.date.issued2012
 
dc.description.abstractVascular endothelial growth factor (VEGF) has a central role in breast cancer development and progression, but the mechanisms that control its expression are poorly understood. Breast cancer tissue microarrays revealed an inverse correlation between the Forkhead transcription factor Forkhead box class O (FOXO)3a and VEGF expression. Using the lapatinib-sensitive breast cancer cell lines BT474 and SKBR3 as model systems, we tested the possibility that VEGF expression is negatively regulated by FOXO3a. Lapatinib treatment of BT474 or SKBR3 cells resulted in nuclear translocation and activation of FOXO3a, followed by a reduction in VEGF expression. Transient transfection and inducible expression experiments showed that FOXO3a represses the proximal VEGF promoter, whereas another Forkhead member, FOXM1, induces VEGF expression. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that both FOXO3a and FOXM1 bind a consensus Forkhead response element (FHRE) in the VEGF promoter. Upon lapatinib stimulation, activated FOXO3a displaces FOXM1 bound to the FHRE before recruiting histone deacetylase 2 (HDAC2) to the promoter, leading to decreased histones H3 and H4 acetylation, and concomitant transcriptional inhibition of VEGF. These results show that FOXO3a-dependent repression of target genes in breast cancer cells, such as VEGF, involves competitive displacement of DNA-bound FOXM1 and active recruitment of transcriptional repressor complexes.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationOncogene, 2012, v. 31 n. 14, p. 1845-1858 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2011.368
 
dc.identifier.citeulike9804826
 
dc.identifier.doihttp://dx.doi.org/10.1038/onc.2011.368
 
dc.identifier.epage1858
 
dc.identifier.hkuros206644
 
dc.identifier.isiWOS:000302785200010
Funding AgencyGrant Number
Cancer Research UK
Breast Cancer Campaign
Portuguese Science and Technology Foundation (FCT)
Funding Information:

This study was supported by the Cancer Research UK (M Petkovic, KK Ho and EW-F Lam), Breast Cancer Campaign (EW-F Lam), the Portuguese Science and Technology Foundation (FCT; AR Gomes).

 
dc.identifier.issn0950-9232
2012 Impact Factor: 7.357
2012 SCImago Journal Rankings: 3.558
 
dc.identifier.issue14
 
dc.identifier.pmcidPMC3232453
 
dc.identifier.pmid21860419
 
dc.identifier.scopuseid_2-s2.0-84860395525
 
dc.identifier.spage1845
 
dc.identifier.urihttp://hdl.handle.net/10722/148691
 
dc.identifier.volume31
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofOncogene
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshBreast Neoplasms - metabolism
 
dc.subject.meshCell Line, Tumor
 
dc.subject.meshForkhead Transcription Factors - metabolism
 
dc.subject.meshGene Expression Regulation, Neoplastic
 
dc.subject.meshVascular Endothelial Growth Factor A - metabolism
 
dc.titleFOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. The University of Hong Kong
  3. Imperial College London