Investigation of novel target genes regulated by polycomb group genes in hepatocellular carcinoma

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PcG proteins form chromatin-associated multiprotein complexes, polycomb repressive complex 1 (PRC1) and PRC2 and repress the expression of targets such as Ink4a/Arf genes. Bmi1, a component of PRC1, has been implicated in the regulation of self-renewal in a range of different stem cells including hepatic stem cells. Analyses of Bmi1-deficient and/or Ink4a/Arf-deficient hepatic stem cells revealed that Bmi1 regulates self-renewal and tumorigenicity in both Ink4a/Arf-dependent and -independent manners. Microarray analyses successfully identified 5 down-regulated genes as candidate downstream targets for Bmi1 such as sex determining region Y-box 17 (Sox17).Loss-of-function assays of Ezh2, a major component of PRC2, also revealed that Ezh2 tightly regulates self-renewal in both normal and cancer stem cells in liver. Moreover, we showed that pharmacological inhibition of EZH2 by an S-adenosylhomocysteine hydrolase inhibitor, 3-deazaneplanocin A (DZNep) is a promising approach for the eradication of liver cancer stem cells.