Epigenetic regulation of liver cancer stem cells and establishment of a novel therapeutic approach

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Polycomb group protein EZH2 is essential for the self-renewal of liver cancer stem cells. Short hairpin-RNA against EZH2 and 3-Deazaneplanocin A (DZNep) promotes the conversion toward differentiated progeny cells and reduced tumorigenic ability thorough the inhibition of H3K27 trimethylation (H3K27me3). We also conducted chromatin immunoprecipitation sequencing (ChIP-seq) analysis of normal hepatic stem cells using anti-H3K27me3 and anti-H3K4me3 antibodies, and successfully identified 562 bivalent genes. In combination with microarray data in the differentiation induction, candidate genes closely associated with hepatocytes and/or cholangiocytes were selected from bivalent genes. Since cancer-related genes were included among these genes, further analyses would be necessary to examine the role of these molecules in normal hepatic stem cells and liver cancer stem cells.