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

Abstract

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.

• Authors: Suresh Bugide, Romi Gupta, Michael R Green, Narendra Wajapeyee
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 30 (07 27 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34301901 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Benzopyrans
• CXCL10 protein, human
• Chemokine CXCL10
• Chemokines
• EED226
• Enzyme Inhibitors
• GSK-2816126
• GSK343
• Indazoles
• Indoles
• Phenols
• Pyridones
• Sulfones
• Triazoles
• theasinensin A
• Decitabine
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• HDAC10 protein, human
• Histone Deacetylases

Topics

• Animals
• Benzopyrans (pharmacology)
• Carcinoma, Hepatocellular (immunology)
• Cell Line, Tumor
• Cell Movement
• Chemokine CXCL10 (genetics, metabolism)
• Chemokines (genetics, metabolism)
• Decitabine (pharmacology)
• Enhancer of Zeste Homolog 2 Protein (genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects, immunology)
• Histone Deacetylases (genetics, metabolism)
• Humans
• Indazoles (pharmacology)
• Indoles (pharmacology)
• Killer Cells, Natural
• Liver Neoplasms
• Male
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental (drug therapy)
• Phenols (pharmacology)
• Pyridones (pharmacology)
• Sulfones (pharmacology)
• Triazoles (pharmacology)