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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / immunology*
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation
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DNA Methyltransferase 3A
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Down-Regulation
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Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
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Enhancer of Zeste Homolog 2 Protein / genetics
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Enhancer of Zeste Homolog 2 Protein / immunology
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GPI-Linked Proteins / genetics
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GPI-Linked Proteins / immunology
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Hep G2 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology
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Killer Cells, Natural / immunology*
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Ligands
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / genetics
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Liver Neoplasms / immunology*
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Liver Neoplasms / pathology
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NK Cell Lectin-Like Receptor Subfamily K / metabolism
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Promoter Regions, Genetic
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Small Molecule Libraries / pharmacology*
Substances
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DNMT3A protein, human
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GPI-Linked Proteins
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Intracellular Signaling Peptides and Proteins
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KLRK1 protein, human
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Ligands
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NK Cell Lectin-Like Receptor Subfamily K
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Small Molecule Libraries
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ULBP1 protein, human
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein