PDF(Pubmed)
Abstract：
Understanding the mechanism of cancer immune surveillance is crucial for precision medicine and effective immunotherapy. We report here that ZNF408, encoded by a gene linked to familial exudative vitreoretinopathy (FEVR) and autosomal recessive retinitis pigmentosa (RP), is physically associated with the SETD1A/COMPASS complex mediating histone H3 lysine 4 (H3K4) methylation in breast cancer cells. Integrative epigenomic and transcriptomic analyses reveal that ZNF408 and SETD1A share overlapped chromatin landscape and coordinately activate a cohort of genes, among which STING1 is critical in innate immune responses. ZNF408-SETD1A complex enhances STING1 expression and promotes STING-mediated anti-tumor immune responses both in vitro and in vivo. Importantly, ZNF408 expression is positively correlated with that of STING1 and negatively correlated with the histological grade of breast cancer. Our study uncovers a role for ZNF408 in cancer immune surveillance, supporting further investigations for therapeutic targeting of ZNF408-SETD1A-STING1 axis in breast carcinogenesis and other ZNF408-associated diseases including FEVR and RP.
摘要：
了解癌症免疫监视的机制对于精准医学和有效的免疫治疗至关重要。我们在这里报道ZNF408，由与家族性渗出性玻璃体视网膜病变（FEVR）和常染色体隐性遗传性色素性视网膜炎（RP）相关的基因编码，与SETD1A/COMPASS复合物介导乳腺癌细胞中组蛋白H3赖氨酸4（H3K4）甲基化相关。整合的表观基因组和转录组分析显示，ZNF408和SETD1A共享重叠的染色质景观，并协调激活一组基因，其中STING1在先天免疫反应中至关重要。ZNF408-SETD1A复合物在体外和体内增强STING1表达并促进STING介导的抗肿瘤免疫应答。重要的是,ZNF408的表达与STING1的表达呈正相关，与乳腺癌的组织学分级呈负相关。我们的研究揭示了ZNF408在癌症免疫监视中的作用，支持ZNF408-SETD1A-STING1轴在乳腺癌发生和其他ZNF408相关疾病（包括FEVR和RP）中的治疗靶向性研究。
