BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10
BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10
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BRMS1L 通过诱导 FZD10 表观遗传沉默来抑制乳腺癌转移。
DOI：
10.1038/ncomms6406
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发表时间：
2014-11-01
影响因子：
16.6
通讯作者：
Song, Erwei
中科院分区：
文献类型：
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作者：
Gong, Chang;Qu, Shaohua;Song, Erwei
BRMS1L （breast cancer metastasis suppressor 1 like, BRMS1-like）是抑制靶基因转录的sin3a -组蛋白去乙酰化酶（HDAC）共抑制因子复合物的一个组分。在这里，我们发现乳腺癌组织中BRMS1L的减少与转移和较差的患者生存有关。功能上，BRMS1L通过抑制上皮-间质转化抑制乳腺癌细胞的迁移和侵袭。这些作用是由FZD10的表观遗传沉默介导的，FZD10是Wnt信号的受体，通过HDAC1募集和启动子上的组蛋白H3K9去乙酰化。因此，brms1l诱导的FZD10沉默抑制了wnt3 -FZD10- β -catenin信号传导的异常激活。此外，BRMS1L是miR-106b的靶点，miR-106b上调导致BRMS1L在乳腺癌细胞中减少。RNA干扰介导的BRMS1L表达沉默促进免疫功能低下小鼠乳腺癌异种移植物的转移，而异位BRMS1L表达抑制转移。因此，BRMS1L在乳腺癌细胞中提供Wnt信号的表观遗传调控，并作为乳腺癌转移抑制因子。
BRMS1L (breast cancer metastasis suppressor 1 like, BRMS1-like) is a component of Sin3A-histone deacetylase (HDAC) co-repressor complex that suppresses target gene transcription. Here we show that reduced BRMS1L in breast cancer tissues is associated with metastasis and poor patient survival. Functionally, BRMS1L inhibits breast cancer cells migration and invasion by inhibiting epithelial-mesenchymal transition. These effects are mediated by epigenetic silencing of FZD10, a receptor for Wnt signalling, through HDAC1 recruitment and histone H3K9 deacetylation at the promoter. Consequently, BRMS1L-induced FZD10 silencing inhibits aberrant activation of WNT3-FZD10-beta-catenin signalling. Furthermore, BRMS1L is a target of miR-106b and miR-106b upregulation leads to BRMS1L reduction in breast cancer cells. RNA interference-mediated silencing of BRMS1L expression promotes metastasis of breast cancer xenografts in immunocompromised mice, whereas ectopic BRMS1L expression inhibits metastasis. Therefore, BRMS1L provides an epigenetic regulation of Wnt signalling in breast cancer cells and acts as a breast cancer metastasis suppressor.