Binding of the JmjC Demethylase JARID1B to LSD1/NuRD Suppresses Angiogenesis and Metastasis in Breast Cancer Cells by Repressing Chemokine CCL14
Binding of the JmjC Demethylase JARID1B to LSD1/NuRD Suppresses Angiogenesis and Metastasis in Breast Cancer Cells by Repressing Chemokine CCL14
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JmjC 去甲基酶 JARID1B 与 LSD1/NuRD 的结合通过抑制趋化因子 CCL14 来抑制乳腺癌细胞的血管生成和转移。
DOI：
10.1158/0008-5472.can-11-1523
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发表时间：
2011-11-01
期刊：
影响因子：
11.2
通讯作者：
Shang, Yongfeng
中科院分区：
文献类型：
--
作者：
Li, Qian;Shi, Lei;Shang, Yongfeng
JARID1B是JmjC/ARID去甲基化酶家族的成员，该家族特异性地去甲基化与活性基因相关的三甲基化和二甲基化形式的组蛋白H3赖氨酸4 （H3K4）。JARID1B在几种癌症中表达失调，但它如何影响肿瘤进展尚不清楚。在这项研究中，我们报道了JARID1B是LSD1/NuRD复合体的一个物理成分，在转录抑制中起作用。JARID1B和LSD1以顺序和协调的方式作用于H3K4去甲基化。全基因组转录分析显示，JARID1B/LSD1/NuRD复合物靶向的细胞信号通路中包括细胞迁移和血管生成的CCL14趋化因子通路。JARID1B抑制CCL14（一种上皮来源的趋化因子）的表达，在体内抑制乳腺癌细胞的血管生成和转移潜能。我们的研究结果表明，CCL14是JARID1B/LSD1/NuRD复合物调控乳腺癌血管生成和转移的关键介质，为乳腺癌干预确定了新的潜在治疗靶点。癌症Res;71 (21);6899 - 908。(c) 2011年aacr。
JARID1B is a member of the JmjC/ARID family of demethylases that specifically demethylates tri- and di-methylated forms of histone H3 lysine 4 (H3K4) that are associated with active genes. JARID1B expression is dysregulated in several cancers in which it has been implicated, but how it might affect tumor progression is unclear. In this study, we report that JARID1B is a physical component of the LSD1/NuRD complex that functions in transcriptional repression. JARID1B and LSD1 acted in a sequential and coordinated manner to demethylate H3K4. A genome-wide transcriptional analysis revealed that among the cellular signaling pathways targeted by the JARID1B/LSD1/NuRD complex is the CCL14 chemokine pathway of cell migration and angiogenesis. JARID1B repressed the expression of CCL14, an epithelial derived chemokine, suppressing the angiogenic and metastatic potential of breast cancer cells in vivo. Our findings indicate that CCL14 is a critical mediator of the JARID1B/LSD1/NuRD complex in regulation of angiogenesis and metastasis in breast cancer, identifying a novel potential therapeutic target for breast cancer intervention. Cancer Res; 71(21); 6899-908. (C) 2011 AACR.