Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells.
Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells.
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DOI：
10.1016/j.celrep.2016.01.056
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发表时间：
2016-02-23
期刊：
影响因子：
8.8
通讯作者：
Conejo-Garcia JR
中科院分区：
文献类型：
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作者：
Tesone AJ;Rutkowski MR;Brencicova E;Svoronos N;Perales-Puchalt A;Stephen TL;Allegrezza MJ;Payne KK;Nguyen JM;Wickramasinghe J;Tchou J;Borowsky ME;Rabinovich GA;Kossenkov AV;Conejo-Garcia JR
特殊的富含AT的序列结合蛋白-1（Satb 1）控制全基因组转录程序。使用一个条件性基因敲除小鼠，我们发现Satb 1是所需的常规树突状细胞（DC）的正常分化。此外，Satb 1通过Notch 1信号传导调节MHC-II表达来控制炎症DC的分化。在机制上，Satb 1结合Notch 1启动子，激活Notch表达并驱动RBPJ占据H2-Ab 1启动子，从而激活MHC-II转录。然而，在浸润卵巢肿瘤的激活的Zbtb 46+炎性DC中肿瘤驱动的Satb 1的持续表达导致免疫抑制表型，其特征在于促肿瘤半乳糖凝集素-1和IL-6的分泌增加。肿瘤相关DC中Satb 1的体内沉默逆转了其致瘤活性并增强了保护性免疫。因此，Satb 1表达的动态波动控制稳态和炎性DC的产生和免疫刺激活性，但在分化的DC中持续Satb 1过表达将其转化为导致恶性进展的致耐受性/促炎细胞。
Special AT-rich sequence-binding protein-1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating MHC-II expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC-II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46+ inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.