Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
Center for Systems and Computational Biology, the Wistar Institute, Philadelphia, PA 19104, USA.
Cell Rep. 2016 Feb 23;14(7):1774-1786. doi: 10.1016/j.celrep.2016.01.056. Epub 2016 Feb 11.
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 major histocompatibility complex class II (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.
富含特殊 AT 的序列结合蛋白 1（Satb1）调控全基因组转录程序。利用条件性基因敲除小鼠，我们发现 Satb1 对于常规树突状细胞（DC）的正常分化是必需的。此外，Satb1 通过 Notch1 信号通路调控主要组织相容性复合体 II（MHC II）的表达来调控炎性 DC 的分化。在机制上，Satb1 结合到 Notch1 启动子上，激活 Notch1 的表达，并驱动 RBPJ 占据 H2-Ab1 启动子，从而激活 MHC II 转录。然而，在浸润卵巢肿瘤的激活的 Zbtb46(+)炎性 DC 中，肿瘤驱动的、持续的 Satb1 表达导致了一种免疫抑制表型，其特征是肿瘤促进因子半乳糖凝集素-1 和 IL-6 的分泌增加。在肿瘤相关 DC 中沉默 Satb1 的体内实验可逆转其致瘤活性并增强保护性免疫。因此，Satb1 表达的动态波动调控着稳态和炎性 DC 的生成和免疫刺激活性，但在分化的 DC 中持续过表达 Satb1 会将其转化为耐受原性/促炎细胞，从而促进恶性进展。
