Acetylation of Snail Modulates the Cytokinome of Cancer Cells to Enhance the Recruitment of Macrophages
Acetylation of Snail Modulates the Cytokinome of Cancer Cells to Enhance the Recruitment of Macrophages
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DOI：
10.1016/j.ccell.2014.09.002
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发表时间：
2014-10-13
期刊：
影响因子：
50.3
通讯作者：
Yang, Muh-Hwa
中科院分区：
文献类型：
--
作者：
Hsu, Dennis Shin-Shian;Wang, Hsiao-Jung;Yang, Muh-Hwa
Snail主要被认为是一种转录抑制因子，通过抑制粘附蛋白诱导上皮-间充质转化。新出现的证据表明，蜗牛可以作为一个激活剂;然而，机制和生物学意义尚不清楚。我们发现CREB结合蛋白（CBP）是Snail介导的靶基因反式激活的关键因子。CBP与Snail相互作用并在赖氨酸146和赖氨酸187处乙酰化Snail，从而阻止阻遏物复合物的形成。我们进一步确定了几个Snail激活的靶点，包括TNF-α，它也是Snail乙酰化的上游信号，以及CCL 2和CCL 5，它们促进肿瘤相关巨噬细胞的募集。在这里，我们提出了我们的研究结果的机制，蜗牛诱导靶基因反式激活重塑肿瘤微环境。
Snail is primarily known as a transcriptional repressor that induces epithelial-mesenchymal transition by suppressing adherent proteins. Emerging evidence suggests that Snail can act as an activator; however, the mechanism and biological significance are unclear. Here, we found that CREB-binding protein (CBP) is the critical factor in Snail-mediated target gene transactivation. CBP interacts with Snail and acetylates Snail at lysine 146 and lysine 187, which prevents the repressor complex formation. We further identified several Snail-activated targets, including TNF-alpha, which is also the upstream signal for Snail acetylation, and CCL2 and CCL5, which promote the recruitment of tumor-associated macrophages. Here, we present our results on the mechanism by which Snail induces target gene transactivation to remodel the tumor microenvironment.