FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer
| Autor: | Janice W. H. Tsang, Aleksandra K. Zwolinska, Anne Feltes, San Yu Wong, Ui-Soon Khoo, Maja Petkovic, Ana R. Gomes, Yuen-Nei Cheung, Christina T. Karadedou, Jie Chen, Eric Lam, Ka-Kei Ho, Jan J. Brosens, Kelvin Y.K. Chan |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Response element TRANSCRIPTION FACTOR FOXO3A Histone Deacetylase 2 GROWTH-INHIBITION CELL BIOLOGY chemistry.chemical_compound LEUKEMIC-CELLS GENETICS & HEREDITY skin and connective tissue diseases GENE-EXPRESSION Histone deacetylase 2 Forkhead Box Protein O3 Forkhead Transcription Factors VEGF SOLID TUMORS DUAL INHIBITOR Gene Expression Regulation Neoplastic Vascular endothelial growth factor Female transcription TYROSINE KINASE INHIBITOR Life Sciences & Biomedicine Biochemistry & Molecular Biology Breast Neoplasms Biology Article breast cancer LUNG-CANCER Cell Line Tumor Genetics Humans Oncology & Carcinogenesis FOXO3a Molecular Biology Transcription factor Science & Technology Forkhead Box Protein M1 Vascular Endothelial Growth Factor A - metabolism FOXM1 1103 Clinical Sciences Lapatinib Breast Neoplasms - metabolism Forkhead Transcription Factors - metabolism ONCOLOGY chemistry Quinazolines Cancer research GEFITINIB IRESSA 1112 Oncology And Carcinogenesis Chromatin immunoprecipitation |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2011.368 |
| Popis: | 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. link_to_OA_fulltext |
| Databáze: | OpenAIRE |
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