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

多梳族基因调控的肝细胞癌新靶基因研究

• 批准号: 21790649
• 负责人: CHIBA Tetsuhiro
• 金额: $ 2.75万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21790649/
• 关键词: 癌幹細胞; 肝臓癌; ポリコーム群遺伝子; 自己複製能; BMI1; EZH2; DZNep

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.

PcG蛋白形成染色质相关的多蛋白复合物，多梳抑制复合物1（PRC 1）和PRC 2，并抑制靶基因如Ink 4a/Arf基因的表达。Bmi 1是PRC 1的一个组成部分，参与了包括肝干细胞在内的一系列不同干细胞自我更新的调节。对Bmi 1缺陷型和/或Ink 4a/Arf缺陷型肝干细胞的分析表明，Bmi 1以Ink 4a/Arf依赖和非依赖的方式调节自我更新和致瘤性。基因芯片分析成功鉴定了5个下调基因作为Bmi 1的候选下游靶点，如性别决定区Y-box 17（Sox 17）。Ezh 2是PRC 2的主要成分，其功能丧失分析也显示Ezh 2在肝脏正常和癌症干细胞中密切调节自我更新。此外，我们表明，药理学抑制EZH 2的S-腺苷高半胱氨酸水解酶抑制剂，3-deazaneplanocin A（DZNep）是一种有前途的方法，用于根除肝癌干细胞。

项目成果

The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells

• DOI: 10.1016/j.jhep.2010.01.027
• 发表时间: 2010-06-01
• 期刊: JOURNAL OF HEPATOLOGY
• 影响因子: 25.7
• 作者: Aoki, Ryutaro;Chiba, Tetsuhiro;Iwama, Atsushi
• 通讯作者: Iwama, Atsushi

Regulation of liver cancer stem cells by polycomb group proteins.

多梳族蛋白对肝癌干细胞的调节。

• 发表时间: 2011
• 作者: 千葉哲博;岩間厚志;横須賀収
• 通讯作者: 横須賀収

Regulatory machinery of Bmil in both normal and cancer stem cells in liver

Bmil 在肝脏正常干细胞和癌症干细胞中的调节机制

• 发表时间: 2009
• 作者: 千葉哲博;青木竜太郎;横須賀収;岩間厚志
• 通讯作者: 岩間厚志

ポリコーム群タンパクによる肝幹細胞の制御機構

多梳蛋白对肝干细胞的调控机制

• 发表时间: 2010
• 作者: 千葉哲博;青木竜太郎;横須賀収
• 通讯作者: 横須賀収

Dmapl plays an essential role in the maintenance of genome integrity through the DNA repair process

Dmapl 通过 DNA 修复过程在维持基因组完整性方面发挥着重要作用

• 发表时间: 2009
• 期刊: Genes to Cells 14
• 作者: Negishi M;et al.
• 通讯作者: et al.