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Article: FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer

TitleFOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer
Authors
Issue Date2012
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2012, v. 31 n. 14, p. 1845-1858 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/148691
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
PubMed Central ID
ISI Accession Number ID
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).

References

 

DC FieldValueLanguage
dc.contributor.authorKaradedou, CTen_US
dc.contributor.authorGomes, ARen_US
dc.contributor.authorChen, Jen_US
dc.contributor.authorPetkovic, Men_US
dc.contributor.authorHo, KKen_US
dc.contributor.authorZwolinska, AKen_US
dc.contributor.authorFeltes, Aen_US
dc.contributor.authorWong, SYen_US
dc.contributor.authorChan, KYKen_US
dc.contributor.authorCheung, YNen_US
dc.contributor.authorTsang, JWHen_US
dc.contributor.authorBrosens, JJen_US
dc.contributor.authorKhoo, USen_US
dc.contributor.authorLam, EWFen_US
dc.date.accessioned2012-05-29T06:14:43Z-
dc.date.available2012-05-29T06:14:43Z-
dc.date.issued2012en_US
dc.identifier.citationOncogene, 2012, v. 31 n. 14, p. 1845-1858en_US
dc.identifier.issn0950-9232en_US
dc.identifier.urihttp://hdl.handle.net/10722/148691-
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.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_US
dc.relation.ispartofOncogeneen_US
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 canceren_US
dc.typeArticleen_US
dc.identifier.emailWong, SY: ashley@pathology.hku.hken_US
dc.identifier.emailChan, KYK: ykchanc@hku.hken_US
dc.identifier.emailCheung, YN: jennyync@hku.hk-
dc.identifier.emailTsang, JWH: jwhtsang@hku.hk-
dc.identifier.emailKhoo, US: uskhoo@hkucc.hku.hk-
dc.identifier.emailLam, EWF: eric.lam@imperial.ac.uk-
dc.identifier.authorityChan, KYK=rp00453en_US
dc.identifier.authorityKhoo, US=rp00362en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1038/onc.2011.368en_US
dc.identifier.pmid21860419-
dc.identifier.pmcidPMC3232453-
dc.identifier.scopuseid_2-s2.0-84860395525-
dc.identifier.hkuros206644-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84859611820&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume31en_US
dc.identifier.issue14en_US
dc.identifier.spage1845en_US
dc.identifier.epage1858en_US
dc.identifier.isiWOS:000302785200010-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.citeulike9804826-

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