File Download
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.1038/onc.2011.368
- Scopus: eid_2-s2.0-84860395525
- PMID: 21860419
- WOS: WOS:000302785200010
- Find via
Supplementary
- Citations:
- Appears in Collections:
Article: FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer
Title | FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer | ||||||||
---|---|---|---|---|---|---|---|---|---|
Authors | |||||||||
Keywords | breast cancer FOXM1 FOXO3a transcription VEGF | ||||||||
Issue Date | 2012 | ||||||||
Publisher | Nature 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? | ||||||||
Abstract | Vascular 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 Identifier | http://hdl.handle.net/10722/148691 | ||||||||
ISSN | 2023 Impact Factor: 6.9 2023 SCImago Journal Rankings: 2.334 | ||||||||
PubMed Central ID | |||||||||
ISI Accession Number ID |
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 Field | Value | Language |
---|---|---|
dc.contributor.author | Karadedou, CT | en_US |
dc.contributor.author | Gomes, AR | en_US |
dc.contributor.author | Chen, J | en_US |
dc.contributor.author | Petkovic, M | en_US |
dc.contributor.author | Ho, KK | en_US |
dc.contributor.author | Zwolinska, AK | en_US |
dc.contributor.author | Feltes, A | en_US |
dc.contributor.author | Wong, SY | en_US |
dc.contributor.author | Chan, KYK | en_US |
dc.contributor.author | Cheung, YN | en_US |
dc.contributor.author | Tsang, JWH | en_US |
dc.contributor.author | Brosens, JJ | en_US |
dc.contributor.author | Khoo, US | en_US |
dc.contributor.author | Lam, EWF | en_US |
dc.date.accessioned | 2012-05-29T06:14:43Z | - |
dc.date.available | 2012-05-29T06:14:43Z | - |
dc.date.issued | 2012 | en_US |
dc.identifier.citation | Oncogene, 2012, v. 31 n. 14, p. 1845-1858 | en_US |
dc.identifier.issn | 0950-9232 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/148691 | - |
dc.description.abstract | Vascular 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.language | eng | en_US |
dc.publisher | Nature Publishing Group. The Journal's web site is located at http://www.nature.com/onc | en_US |
dc.relation.ispartof | Oncogene | en_US |
dc.subject | breast cancer | - |
dc.subject | FOXM1 | - |
dc.subject | FOXO3a | - |
dc.subject | transcription | - |
dc.subject | VEGF | - |
dc.subject.mesh | Breast Neoplasms - metabolism | - |
dc.subject.mesh | Cell Line, Tumor | - |
dc.subject.mesh | Forkhead Transcription Factors - metabolism | - |
dc.subject.mesh | Gene Expression Regulation, Neoplastic | - |
dc.subject.mesh | Vascular Endothelial Growth Factor A - metabolism | - |
dc.title | FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer | en_US |
dc.type | Article | en_US |
dc.identifier.email | Wong, SY: ashley@pathology.hku.hk | en_US |
dc.identifier.email | Chan, KYK: ykchanc@hku.hk | en_US |
dc.identifier.email | Cheung, YN: jennyync@hku.hk | - |
dc.identifier.email | Tsang, JWH: jwhtsang@hku.hk | - |
dc.identifier.email | Khoo, US: uskhoo@hkucc.hku.hk | - |
dc.identifier.email | Lam, EWF: eric.lam@imperial.ac.uk | - |
dc.identifier.authority | Chan, KYK=rp00453 | en_US |
dc.identifier.authority | Khoo, US=rp00362 | en_US |
dc.description.nature | link_to_OA_fulltext | en_US |
dc.identifier.doi | 10.1038/onc.2011.368 | en_US |
dc.identifier.pmid | 21860419 | - |
dc.identifier.pmcid | PMC3232453 | - |
dc.identifier.scopus | eid_2-s2.0-84860395525 | - |
dc.identifier.hkuros | 206644 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-84859611820&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 31 | en_US |
dc.identifier.issue | 14 | en_US |
dc.identifier.spage | 1845 | en_US |
dc.identifier.epage | 1858 | en_US |
dc.identifier.isi | WOS:000302785200010 | - |
dc.publisher.place | United Kingdom | en_US |
dc.identifier.citeulike | 9804826 | - |
dc.identifier.issnl | 0950-9232 | - |