Journal Article

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

Wajapeyee, Narendra, Green, Michael R., Bugide, Suresh

2018

Overview

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 downregulation 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.

• Publisher: National Academy of Sciences
• Subject: Biological Sciences / Cancer / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - immunology / Carcinoma, Hepatocellular - pathology / Cell Line, Tumor / Cells / Clinical trials / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA Methylation / Down-Regulation / Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors / Enhancer of Zeste Homolog 2 Protein - genetics / Enhancer of Zeste Homolog 2 Protein - immunology / Gene regulation / GPI-Linked Proteins - genetics / GPI-Linked Proteins - immunology / Hep G2 Cells / Hepatocellular carcinoma / Homology / Humans / Immune response / Immune system / Inhibitors / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - immunology / Killer Cells, Natural - immunology / Ligands / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - genetics / Liver Neoplasms - immunology / Liver Neoplasms - pathology / Lymphoma / Medical Sciences / Natural killer cells / NK Cell Lectin-Like Receptor Subfamily K - metabolism / NKG2 antigen / Organic chemistry / PNAS Plus / Promoter Regions, Genetic / Small Molecule Libraries - pharmacology / Transcription / Tumors