Enhancer of zeste homolog 2 (EZH2) is a histone H3 lysine 27 methyltransferase that has been shown to function as an oncogene in some cancers. Previous reports have largely focused on the ability of EZH2 to regulate cell-intrinsic tumor regulatory pathways as its mechanism-of-oncogenic action. However, the role that EZH2-mediated immune suppression plays in its oncogenic activity is not fully known. In particular, the role of natural killer (NK) cells in EZH2-driven tumor growth remains incompletely understood. Here, we demonstrate that genetic or pharmacological inhibition of EZH2 induces reexpression of the chemokine CXCL10 in hepatic tumor cells. We find that histone deacetylase 10 (HDAC10) is necessary for EZH2 recruitment to the CXCL10 promoter, leading to CXCL10 transcriptional repression. Critically, CXCL10 is necessary and sufficient for stimulating NK cell migration, and EZH2’s ability to inhibit NK cell migration via CXCL10 suppression is conserved in other EZH2-dependent cancers. NK cell depletion in an immunocompetent syngeneic mouse model of hepatic tumorigenesis reverses the tumor inhibitory effects of an EZH2 inhibitor (GSK343), and inhibitor-mediated reexpression of CXCL10 is required for its tumor suppressive effects in the same mouse model. Collectively, these results reveal a decisive role for NK cells and CXCL10 in mediating the oncogenic function of EZH2.

zeste 同源物 2 (EZH2) 的增强子是一种组蛋白 H3 赖氨酸 27 甲基转移酶，已被证明在某些癌症中起癌基因的作用。以前的报告主要集中在 EZH2 调节细胞内在肿瘤调节途径的能力作为其致癌作用的机制。然而，EZH2 介导的免疫抑制在其致癌活性中所起的作用尚不完全清楚。特别是，自然杀伤 (NK) 细胞在 EZH2 驱动的肿瘤生长中的作用仍未完全了解。在这里，我们证明 EZH2 的遗传或药理学抑制诱导趋化因子 CXCL10 在肝肿瘤细胞中的重新表达。我们发现组蛋白去乙酰化酶 10 (HDAC10) 是 EZH2 募集到CXCL10启动子所必需的，导致CXCL10转录抑制。至关重要的是，CXCL10 对于刺激 NK 细胞迁移是必要和充分的，而 EZH2 通过 CXCL10 抑制来抑制 NK 细胞迁移的能力在其他 EZH2 依赖性癌症中是保守的。在具有免疫活性的肝肿瘤发生同基因小鼠模型中，NK 细胞耗竭逆转了 EZH2 抑制剂 (GSK343) 的肿瘤抑制作用，并且在同一小鼠模型中，CXCL10 的肿瘤抑制作用需要抑制剂介导的再表达。总的来说，这些结果揭示了 NK 细胞和 CXCL10 在介导 EZH2 的致癌功能中的决定性作用。