EZH2 inhibits NK cell-mediated antitumor immunity by suppressing CXCL10 expression in an HDAC10-dependent manner
EZH2 inhibits NK cell-mediated antitumor immunity by suppressing CXCL10 expression in an HDAC10-dependent manner
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DOI：
10.1073/pnas.2102718118
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发表时间：
2021-07-27
影响因子：
11.1
通讯作者：
Wajapeyee, Narendra
中科院分区：
文献类型：
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作者：
Bugide, Suresh;Gupta, Romi;Wajapeyee, Narendra
zeste增强子同源物2（EZH2）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作为致癌基因发挥作用。以前的报道主要集中在EZH2调节细胞内源性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不完全清楚。在这里，我们证明了EZH2的遗传或药理学抑制诱导肝肿瘤细胞中趋化因子CXCL10的再表达。我们发现，组蛋白去乙酰化酶10（HDAC10）是必需的EZH2招聘到CXCL10启动子，导致CXCL10转录抑制。重要的是，CXCL10对于刺激NK细胞迁移是必要的和足够的，并且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。肝脏肿瘤发生的免疫活性同基因小鼠模型中的NK细胞耗竭逆转了EZH2抑制剂（GSK 343）的肿瘤抑制作用，并且抑制剂介导的CXCL 10的再表达是其在相同小鼠模型中的肿瘤抑制作用所必需的。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。
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 EZH2mediated immune suppression plays in its oncogenic activity is not fully known. In particular, the role of natural killer (NK) cells in EZH2driven 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 EZH2dependent 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.