Sauer M, Schuldner M, Hoffmann N, Cetintas A, Reiners K S, Shatnyeva O, Hallek M, Hansen H P, Gasser S, von Strandmann E P
Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
Oncogene. 2017 Feb 16;36(7):933-941. doi: 10.1038/onc.2016.259. Epub 2016 Aug 1.
Tumor surveillance of natural killer (NK) cells is mediated by the cytotoxicity receptor natural-killer group 2 member D (NKG2D). Ligands for NKG2D are generally not expressed on healthy cells, but induced on the surface of malignant cells. To date, NKG2D ligand (NKG2D-L) induction was mainly described to depend on the activation of the DNA damage response, although the molecular mechanisms that regulate NKG2D-L expression remain largely unknown. Here, we show that the acetyltransferases CBP (CREB-binding protein) and p300 play a crucial role in the regulation of NKG2D-L on tumor cells. Loss of CBP/p300 decreased the basal cell surface expression of human ligands and reduced the upregulation of MICA/B and ULBP2 in response to histone deacetylase inhibitors or DNA damage. Furthermore, CBP/P300 deficiency abrogated the sensitivity of stressed cells to NK cell-mediated killing. CBP/p300 were also identified as major regulators of mouse NKG2D ligand RAE-1 in vitro and in vivo using the Eμ-Myc lymphoma model. Mechanistically, we observed an enhanced activation of the CBP/p300 binding transcription factor CREB (cAMP response element-binding protein) correlating to the NKG2D-L upregulation. Moreover, increased binding of CREB and CBP/p300 to NKG2D-L promoters and elevated histone acetylation were detectable. This study provides strong evidence for a major role of CBP and p300 in orchestrating NKG2D-L induction and consequently immunosurveillance of tumors in mice and humans. These findings might help to develop novel immunotherapeutic approaches against cancer.
自然杀伤（NK）细胞的肿瘤监视作用由细胞毒性受体自然杀伤细胞2族成员D（NKG2D）介导。NKG2D的配体通常不在健康细胞上表达，但在恶性细胞表面被诱导表达。迄今为止，NKG2D配体（NKG2D-L）的诱导主要被描述为依赖于DNA损伤反应的激活，尽管调节NKG2D-L表达的分子机制在很大程度上仍不清楚。在这里，我们表明乙酰转移酶CBP（CREB结合蛋白）和p300在肿瘤细胞中NKG2D-L的调节中起关键作用。CBP/p300的缺失降低了人类配体的基础细胞表面表达，并减少了对组蛋白去乙酰化酶抑制剂或DNA损伤的MICA/B和ULBP2的上调。此外，CBP/P300缺陷消除了应激细胞对NK细胞介导杀伤的敏感性。使用Eμ-Myc淋巴瘤模型，CBP/p300在体外和体内也被确定为小鼠NKG2D配体RAE-1的主要调节因子。从机制上讲，我们观察到与NKG2D-L上调相关的CBP/p300结合转录因子CREB（cAMP反应元件结合蛋白）的激活增强。此外，可检测到CREB和CBP/p300与NKG2D-L启动子的结合增加以及组蛋白乙酰化升高。这项研究为CBP和p300在协调NKG2D-L诱导从而在小鼠和人类肿瘤免疫监视中发挥主要作用提供了有力证据。这些发现可能有助于开发针对癌症的新型免疫治疗方法。
