FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells
FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells
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DOI：
10.1007/s10549-011-1396-3
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发表时间：
2012-01-01
影响因子：
3.8
通讯作者：
Lu, Jun
中科院分区：
文献类型：
--
作者：
Du, Juan;Li, Lin;Lu, Jun
多梳族 (PcG) 蛋白最近被证明与癌症的发生有关。 PcG 蛋白 EZH2 参与前列腺癌和乳腺癌的进展，并已被确定为乳腺癌的分子标志物。然而，PcG蛋白调节癌症进展和恶性转移的分子机制仍不清楚。 PcG 蛋白使未分化上皮细胞中的 H3K27 甲基化，从而抑制 HOX 等分化基因。 FOXC1 是 Forkhead box 转录因子家族的成员，在分化中发挥重要作用，并参与眼睛发育。我们在这项研究中发现，在MCF-7和MDA-MB-231细胞中，FOXC1基因的表达与PcG基因（即Bmi1、EZH2和SUZ12）的表达呈负相关。为了研究PcG蛋白对FOXC1基因的调控作用，将Bmi1、EZH2和SUZ12的表达质粒或siRNA质粒转染这两个细胞系，我们发现PcG，尤其是EZH2，可以抑制FOXC1基因的转录。染色质免疫沉淀 (ChIP) 测定表明组蛋白甲基化和乙酰化修饰在此调节过程中发挥着关键作用。当FOXC1稳定转染MDA-MB-231细胞时，细胞的迁移和侵袭受到抑制。此外，利用FOXC1-MDA-MB-231HM和GFP-MDA-MB-231HM细胞的无胸腺小鼠正交异种异种移植肿瘤模型测定了FOXC1调节的致瘤性和自发转移能力，结果表明FOXC1在体外抑制MDA-MB-231HM细胞的迁移和侵袭，并降低了细胞的迁移和侵袭能力。 体内肺转移。本报告中提供的数据有助于理解 EZH2 参与肿瘤发展的机制。
Polycomb group (PcG) proteins have recently been shown related to cancer development. The PcG protein EZH2 is involved in progression of prostate and breast cancers, and has been identified as a molecular marker in breast cancer. Nevertheless, the molecular mechanism by which PcG proteins regulate cancer progression and malignant metastasis is still unclear. PcG proteins methylate H3K27 in undifferentiated epithelial cells, resulting in the repression of differentiation genes such as HOX. FOXC1 is a member of the Forkhead box transcription factor family, which plays an important role in differentiation, and is involved in eye development. We discovered in this study that the expression of FOXC1 gene was negatively correlated to that of PcG genes, i.e., Bmi1, EZH2, and SUZ12, in MCF-7 and MDA-MB-231 cells. To investigate the regulatory effects of PcG proteins on FOXC1 gene, the two cell lines were transfected with either expression plasmids or siRNA plasmids of Bmi1, EZH2, and SUZ12, and we found that PcGs, especially EZH2, could repress the transcription of FOXC1 gene. Chromatin immunoprecipitation (ChIP) assay showed that histone methylation and acetylation modifications played critical roles in this regulatory process. When FOXC1 was stably transfected into MDA-MB-231 cells, the migration and invasion of the cells were repressed. Moreover, the tumorigenicity and the spontaneous metastatic capability regulated by FOXC1 were determined by using an orthotropic xenograft tumor model of athymic mice with the FOXC1-MDA-MB-231HM and the GFP-MDA-MB-231HM cells, and the results showed that FOXC1 in MDA-MB-231HM cells inhibited migration and invasion in vitro and reduced the pulmonary metastasis in vivo. Data presented in this report contribute to the understanding of the mechanisms by which EZH2 participates in tumor development.