EZH2 inhibits NK cell–mediated antitumor immunity by suppressing CXCL10 expression in an HDAC10-dependent manner
Menée in vitro et à l'aide d'un modèle murin de tumeur hépatique, cette étude met en évidence un mécanisme par lequel la méthyltransférase EZH2, en supprimant l'expression du ligand CXCL10 via l'histone désacétylase 10, inhibe l'immunité antitumorale induite par les cellules NK
Hepatocellular carcinoma (HCC), a type of liver cancer, has a poor 5-y survival rate and current therapies provide only marginal clinical benefits to most HCC patients. Therefore, new therapeutic approaches are needed for HCC treatment. Natural killer (NK) cells are cells of the innate immune system that can inhibit tumor development and progression. We find that pharmacological inhibition of EZH2 results in NK cell–mediated hepatic tumor growth inhibition in mice, which occurs, in part, due to the increased expression of the chemokine CXCL10, leading to increased NK cell migration. These results have implications for EZH2-dependent tumors, in which NK cell–mediated tumor clearance can be induced using EZH2 inhibitors.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.RNA-seq data of this study have been submitted to the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO), https://www.ncbi.nlm.nih.gov/geo/ (accession no. GSE166553) (57). All additional data discussed in the paper are available in the main text and SI Appendix.