Functional analysis epigenetics regulators in carcinogenesis

致癌作用中表观遗传学调控因子的功能分析

• 批准号: 18590066
• 负责人: OSADA Shigehiro
• 金额: $ 2.59万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590066/
• 关键词: chromatin; histone; epignetics; acetylation; histone variant; gene expression; carcinogenesis; tumor marker; 脱アセチル化; ヒストン修飾; 化学発がん; 前がん病変

Great effort has been directed towards understanding the mechanism of malignant transformation derived from genetic mutations. Nowadays, studies on epigenetic mutations in cancer are also required. In this project, we focused on epigenetics modulators (histone modification enzymes and histone variants), up-regulated during chemically induced hepatocarcinogenesis.1. Effect of over expression of histone modification enzymes on the malignant transformation.We identified histone modification enzymes, which induced during hepatocarcinogenesis by RT-PCR, DNA microarray, and Western blot analyses. One of them, histone acetyltransferase, regulated the transformation activity mediated by mutated ras oncogene. Histone deacetylase, one of other modulators, promoted anchorage independent growth in soft agarose.2. Effect of over expression of histone modification enzymes on expression of the tumor marker gene.Glutathione transferase placental form (GST-P) is specifically dramatically induced during … More hepatocarcinogenesis and recognized as a reliable tumor marker. Transcriptional factor Nrf2/MafK heterodimer is one of the most important positive regulators on GST-P expression during hepatocarcinogenesis. We revealed that one of histone acetyltransferase, which was over-expressed in nuclear extracts from livers including hyperplastic nodules, acted as a cofactor of Nrf2/MafK heterodimer and induced expression of GST-P.3. Functional analysis of the histone variant in yeast.We found that H2A.Z, one of histone variants, was induced during hepatocarcinogenesis. Tb gain insights of molecular function of H2A.Z, we generated a H2A.Z deletion strain in Saccharomyces cerevisiae. The H2A.Z deletion strain was sensitive to genotoxic reagents. Further, we observed the sensitivity to nickel compounds, which decrease acetylation levels of all four histones and increase ubiquitylation of H2A and H2B and dimethylation of H3 lysine 9, and revealed that the nickel toxicity appeared with the incorporation of H2AZ into chromatin mediated by the chromatin remodeling factor, but not acetylation of H2AZ. Less

人们一直致力于了解基因突变导致恶性转化的机制。如今，还需要对癌症的表观遗传突变进行研究。在这个项目中，我们专注于表观遗传学调节剂（组蛋白修饰酶和组蛋白变体），在化学诱导的肝癌发生过程中上调。组蛋白修饰酶过度表达对肝癌发生的影响我们通过RT-PCR、DNA微阵列和Western印迹分析鉴定了肝癌发生过程中诱导的组蛋白修饰酶。其中组蛋白乙酰转移酶调节突变ras癌基因介导的转化活性。组蛋白去乙酰化酶是另一种促进软琼脂糖贴壁生长的调节因子.组蛋白修饰酶的过度表达对肿瘤标志物基因表达的影响：胎盘型谷胱甘肽转移酶（GST-P）在肿瘤发生过程中被特异性地显著诱导。 ...更多信息 肝癌发生，被认为是可靠的肿瘤标志物。转录因子Nrf 2/MafK异源二聚体是肝癌发生过程中GST-P表达的重要正调控因子之一。我们发现，组蛋白乙酰转移酶，这是过表达的核提取物，从肝脏包括增生结节，作为一个辅因子的Nrf 2/MafK异源二聚体和诱导表达的GST-P。酵母中组蛋白变异体的功能分析：我们发现组蛋白变异体H2 A. Z在肝癌发生过程中被诱导。为了深入了解H2 A. Z的分子功能，我们在酿酒酵母中构建了一株H2 A. Z缺失菌株。H2A.Z缺失株对遗传毒性试剂敏感。此外，我们观察到对镍化合物的敏感性，这降低了所有四种组蛋白的乙酰化水平，增加了H2 A和H2 B的泛素化以及H3赖氨酸9的二甲基化，并揭示了镍毒性出现在由染色质重塑因子介导的H2 AZ掺入染色质中，而不是H2 AZ的乙酰化。少

项目成果

Histone acetyltransferase MOZ is induced during hepatocarcinogenesis, acts as a coactivator of Nrf2/MafK and induces tumor marker gene expression.

组蛋白乙酰转移酶 MOZ 在肝癌发生过程中被诱导，作为 Nrf2/MafK 的共激活剂并诱导肿瘤标志物基因表达。

• 发表时间: 2007
• 期刊: Biochemical Journal 402・3
• 作者: K.Enya;et. al.;礒浜 洋一郎(第一著者名);Kumiko Ohta
• 通讯作者: Kumiko Ohta

Histone acetyltransferase MOZ is induced during hepatocarcinogenesis, acts as a coactivator of Nrf2/MafK and induces tumor marker gene expression

组蛋白乙酰转移酶 MOZ 在肝癌发生过程中被诱导，作为 Nrf2/MafK 的共激活剂并诱导肿瘤标志物基因表达

• 发表时间: 2007
• 期刊: Biochemical Journal 402
• 作者: Kumiko;Ohta
• 通讯作者: Ohta

Altered gene expression of transcriptional regulatory factors in tumor marker-positive cells during chemically induced hepatocarcinogenes

化学诱导肝癌过程中肿瘤标志物阳性细胞转录调控因子基因表达的改变

• 发表时间: 2006
• 期刊: Toxicology Letters 167
• 作者: Isohama;Y.;Nomura;J.;Harada;S.;Hisatsune;A.;Katsuki;H.;Miyata;T.;Shigehiro Osada
• 通讯作者: Shigehiro Osada

ニッケル感受性を利用したヒストンバリアントH2A. Zの機能解析

使用镍敏感性对组蛋白变体 H2A.Z 进行功能分析

• 发表时间: 2007
• 作者: 藤井 暢弘;横田 伸一;横沢 紀子;岡林 環樹;五味田 麗
• 通讯作者: 五味田 麗

FAD24, a regulator of adipogenesis and DNA replication, inhibits H-RAS-mediated transformation by repressing NF-κB activity.

FAD24 是脂肪生成和 DNA 复制的调节剂，通过抑制 NF-κB 活性来抑制 H-RAS 介导的转化。

• 发表时间: 2008
• 期刊: Biochem. Biophys. Res. Commun. 369
• 作者: Johmura;Y.
• 通讯作者: Y.