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Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation.
Cell Reports ( IF 7.5 ) Pub Date : 2019-04-02 , DOI: 10.1016/j.celrep.2019.03.008
Denise E de Almeida Nagata 1 , Eugene Y Chiang 1 , Suchit Jhunjhunwala 2 , Patrick Caplazi 3 , Vidhyalakshmi Arumugam 1 , Zora Modrusan 4 , Emily Chan 5 , Mark Merchant 5 , Lingyan Jin 6 , David Arnott 7 , F Anthony Romero 8 , Steven Magnuson 8 , Karen E Gascoigne 6 , Jane L Grogan 1
Affiliation  

Myeloid-derived suppressor cells (MDSCs) are found in most cancer malignancies and support tumorigenesis by suppressing immunity and promoting tumor growth. Here we identify the bromodomain (BRD) of CBP/EP300 as a critical regulator of H3K27 acetylation (H3K27ac) in MDSCs across promoters and enhancers of pro-tumorigenic target genes. In preclinical tumor models, in vivo administration of a CBP/EP300-BRD inhibitor (CBP/EP300-BRDi) alters intratumoral MDSCs and attenuates established tumor growth in immunocompetent tumor-bearing mice, as well as in MDSC-dependent xenograft models. Inhibition of CBP/EP300-BRD redirects tumor-associated MDSCs from a suppressive to an inflammatory phenotype through downregulation of STAT pathway-related genes and inhibition of Arg1 and iNOS. Similarly, CBP/EP300-BRDi decreases differentiation and suppressive function of human MDSCs in vitro. Our findings uncover a role of CBP/EP300-BRD in intratumoral MDSCs that may be targeted therapeutically to boost anti-tumor immunity.

中文翻译:

通过H3K27乙酰化的CBP / EP300溴结构域调节来调节肿瘤相关的髓样细胞活性。

髓样来源的抑制细胞(MDSC)被发现在大多数癌症恶性肿瘤中,并通过抑制免疫力和促进肿瘤生长来支持肿瘤发生。在这里,我们确定CBP / EP300的溴结构域(BRD)是MDSC中跨致瘤性靶基因启动子和增强子的H3K27乙酰化(H3K27ac)的关键调节剂。在临床前肿瘤模型中,体内施用CBP / EP300-BRD抑制剂(CBP / EP300-BRDi)会改变肿瘤内MDSC的存在,并减弱具有免疫功能的荷瘤小鼠以及依赖MDSC的异种移植模型中已建立的肿瘤生长。CBP / EP300-BRD的抑制通过下调STAT通路相关基因并抑制Arg1和iNOS,将肿瘤相关MDSCs从抑制表型重定向到炎症表型。相似地,CBP / EP300-BRDi在体外降低人MDSC的分化和抑制功能。我们的发现揭示了CBP / EP300-BRD在肿瘤内MDSC中的作用,该药物可能在治疗上针对增强抗肿瘤免疫力。
更新日期:2019-04-03
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