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, J2 3
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
2011 Impact Factor: 6.373
2011 SCImago Journal Rankings: 1.216
DOIhttp://dx.doi.org/10.1038/onc.2011.368
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).

PubMed Central IDPMC3232453
ReferencesReferences in Scopus
DC Field
Value
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
2011 Impact Factor: 6.373
2011 SCImago Journal Rankings: 1.216
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
Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. The University of Hong Kong
  3. Imperial College London