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Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):E3509-E3518. doi: 10.1073/pnas.1802691115. Epub 2018 Mar 26.

Inhibition of Enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
2
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; narendra.wajapeyee@yale.edu michael.green@umassmed.edu.
3
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605.
4
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510; narendra.wajapeyee@yale.edu michael.green@umassmed.edu.

Abstract

Natural killer (NK) cell-mediated tumor cell eradication could inhibit tumor initiation and progression. However, the factors that regulate NK cell-mediated cancer cell eradication remain unclear. We determined that hepatocellular carcinoma (HCC) cells exhibit transcriptional down-regulation of NK group 2D (NKG2D) ligands and are largely resistant to NK cell-mediated eradication. Because the down-regulation of NKG2D ligands occurred at the transcriptional level, we tested 32 chemical inhibitors of epigenetic regulators for their ability to re-express NKG2D ligands and enhance HCC cell eradication by NK cells and found that Enhancer of zeste homolog 2 (EZH2) was a transcriptional repressor of NKG2D ligands. The inhibition of EZH2 by small-molecule inhibitors or genetic means enhanced HCC cell eradication by NK cells in a NKG2D ligand-dependent manner. Collectively, these results demonstrate that EZH2 inhibition enhances HCC eradication by NK cells and that EZH2 functions, in part, as an oncogene by inhibiting immune response.

KEYWORDS:

DNMT3A; EZH2; HCC; NK cell ligands; NK cells

PMID:
29581297
PMCID:
PMC5899497
DOI:
10.1073/pnas.1802691115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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