FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer.
FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer.
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DOI：
10.1038/onc.2011.368
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发表时间：
2012-04-05
期刊：
影响因子：
8
通讯作者：
Lam, E. W-F
中科院分区：
文献类型：
--
作者：
Karadedou, C. T.;Gomes, A. R.;Chen, J.;Petkovic, M.;Ho, K-K;Zwolinska, A. K.;Feltes, A.;Wong, S. Y.;Chan, K. Y. K.;Cheung, Y-N;Tsang, J. W. H.;Brosens, J. J.;Khoo, U-S;Lam, E. W-F
血管内皮生长因子（VEGF）在乳腺癌的发生和发展中起着重要作用，但其表达的调控机制尚不清楚。乳腺癌组织微阵列显示叉头转录因子FOXO3a和VEGF表达之间呈负相关。使用拉帕替尼敏感的乳腺癌细胞系BT474和SKBR 3作为模型系统，我们测试了VEGF表达受FOXO 3a负调控的可能性。拉帕替尼处理BT474或SKBR 3细胞导致核转位和FOXO 3a活化，随后VEGF表达降低。瞬时转染和诱导表达实验表明，FOXO 3a抑制近端VEGF启动子，而另一个叉头成员，FOXM 1，诱导VEGF表达。染色质免疫沉淀和寡核苷酸下拉分析表明，FOXO 3a和FOXM 1结合的共识叉头反应元件（FHRE）的VEGF启动子。拉帕替尼刺激后，激活的FOXO3a取代结合FHRE的FOXM1，然后将组蛋白脱乙酰酶2（HDAC 2）募集到启动子，导致组蛋白H3和H4乙酰化降低，并伴随VEGF的转录抑制。这些结果表明，乳腺癌细胞中靶基因（如VEGF）的FOXO 3a依赖性抑制涉及DNA结合的FOXM 1的竞争性置换和转录抑制因子复合物的主动募集。
Vascular endothelial growth factor (VEGF) plays 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 FOXO3a 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 demonstrated 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.
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