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

PCG蛋白形成染色质相关的多蛋白复合体、多梳抑制复合体1(PRC1)和PrC2，并抑制Ink4a/Arf基因等靶基因的表达。BMI1是PRC1的一种成分，参与了包括肝脏干细胞在内的一系列不同干细胞的自我更新调节。对Bmi1缺陷和/或Ink4a/Arf缺陷的肝干细胞的分析表明，Bmi1以Ink4a/Arf依赖和非依赖的方式调节自我更新和致瘤性。微阵列分析成功地确定了5个下调的基因作为Bmi1的候选下游靶基因，如性别决定区Y-box 17(Sox17)。对PRC2的主要成分Ezh2的功能丧失分析也表明，Ezh2严格调控肝脏正常和肿瘤干细胞的自我更新。此外，我们还表明，S-腺苷同型半胱氨酸水解酶抑制剂3-去氮杂环素A(DZNep)对EZH_2的药理抑制是一种有希望的根除肝癌干细胞的方法。

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.