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

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.

• Authors: Suresh Bugide, 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. 115 Issue 15 Pg. E3509-E3518 (04 10 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29581297 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNMT3A protein, human
• GPI-Linked Proteins
• Intracellular Signaling Peptides and Proteins
• KLRK1 protein, human
• Ligands
• NK Cell Lectin-Like Receptor Subfamily K
• Small Molecule Libraries
• ULBP1 protein, human
• DNA (Cytosine-5-)-Methyltransferases
• DNA Methyltransferase 3A
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein

Topics

• Carcinoma, Hepatocellular (drug therapy, genetics, immunology, pathology)
• Cell Line, Tumor
• DNA (Cytosine-5-)-Methyltransferases (metabolism)
• DNA Methylation
• DNA Methyltransferase 3A
• Down-Regulation
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors, genetics, immunology)
• GPI-Linked Proteins (genetics, immunology)
• Hep G2 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, immunology)
• Killer Cells, Natural (immunology)
• Ligands
• Liver Neoplasms (drug therapy, genetics, immunology, pathology)
• NK Cell Lectin-Like Receptor Subfamily K (metabolism)
• Promoter Regions, Genetic
• Small Molecule Libraries (pharmacology)