EZH2 inhibits NK cell-mediated antitumor immunity by suppressing CXCL10 expression in an HDAC10-dependent manner

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.

Automated summary

EZH2 has been shown to function as an oncogene in some cancers, mainly through regulating cell-intrinsic tumor regulatory pathways. However, the role of EZH2-mediated immune suppression, particularly regarding natural killer (NK) cells, in its oncogenic activity is not fully understood. In this study, it was revealed that EZH2 inhibition induced reexpression of chemokine CXCL10 in hepatic tumor cells, which in turn stimulated NK cell migration and reversed tumor growth. This suggests a crucial role for NK cells and CXCL10 in mediating the oncogenic function of EZH2.