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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: Karadedou, CT
Gomes, AR
Chen, J
Petkovic, M
Ho, KK
Zwolinska, AK
Feltes, A
Wong, SY
Chan, KY
Cheung, YN
Tsang, JW
Brosens, JJ
Khoo, US
Lam, EW
Item Type: Journal Article
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.Oncogene advance online publication, 22 August 2011; doi:10.1038/onc.2011.368.
Issue Date: 22-Aug-2011
Date of Acceptance: 30-Jun-2011
URI: http://hdl.handle.net/10044/1/39185
DOI: http://dx.doi.org/10.1038/onc.2011.368
ISSN: 1476-5594
Publisher: Nature Publishing Group
Start Page: 1845
End Page: 1858
Journal / Book Title: Oncogene
Volume: 31
Issue: 14
Copyright Statement: © 2012 Macmillan Publishers Limited. All rights reserved.
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
GENETICS & HEREDITY
ONCOLOGY
VEGF
FOXO3a
FOXM1
breast cancer
transcription
TYROSINE KINASE INHIBITOR
TRANSCRIPTION FACTOR FOXO3A
LEUKEMIC-CELLS
GROWTH-INHIBITION
GEFITINIB IRESSA
GENE-EXPRESSION
DUAL INHIBITOR
SOLID TUMORS
LUNG-CANCER
LAPATINIB
Breast Neoplasms
Cell Line, Tumor
Female
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Histone Deacetylase 2
Humans
Quinazolines
Vascular Endothelial Growth Factor A
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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