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Roles of Histone Methyltransferase in Human Cancer

组蛋白甲基转移酶在人类癌症中的作用

基本信息

批准号：
18590393
负责人：
KONDO Yutaka
金额：
$ 2.55万
依托单位：
Aichi Cancer Center Research Institute
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

项目摘要

Modifications of the histone amino-terminal tails affect access of regulatory factors and complexes to chromatin and thereby influence biological processes. Cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications as well as DNA methylation However, the functional roles of the histone methyltransferases(HMT) in cancer remain unclear.First, we examined histone modification changes and DNA methylation in hepatocellular carcinomas(HCC). Aberrant DNA methylation was frequently detected in all the HCC. Epigenetic states in HCC cell lines showed that silencing of P16 and RASSF1a depended on DNA methylation and histone H3-lysine(K) 9 methylataon. However, silencing of the PGR and Erα genes was more closely related to H3-K27 methylation rather than DNA methylation Consistent with the alteration of histone status, higher expression of G9a and EZH2 was found in HCC than in non-cancerous liver tissues(P < 0.01) These data suggest that multiple epigenet … More ic silencing mechanisms are inappropriately active in HCC cells.Next, We studied RNAi-based inhibition(knockdown, KD) of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the two HMTs in PC3 cancer cell line markedly inhibited cell growth and caused profound morphological changes with loss of telomerase activity and shortened telomeres. SUV39H1 KD cells showed substantial increase in G2/M fraction. Karyotype analyses showed that this was due to an increased number of chromosomes in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in the G9a KD cells, while centrosomes were morphologically normal in control cells. These data suggest that the 2 HMTs, SUV39H1 and G9a are required to perpetuate the malignant phenotype. Furthermore, G9a plays a critical role in regulating centrosome duplication presumably through chromatin structure rather than through affecting gene expression in cancer cells. Targeting these histone methyltransferases may be of therapeutic benefit in cancers Less

组蛋白氨基末端尾部的修饰影响调节因子和复合物进入染色质，从而影响生物学过程。癌细胞具有明显的表观遗传异常，包括组蛋白修饰和DNA甲基化。然而，组蛋白甲基转移酶（HMT）在癌症中的功能作用尚不清楚。DNA甲基化异常在所有HCC中均常见。肝癌细胞系的表观遗传状态表明，P16和RASSF 1a的沉默依赖于DNA甲基化和组蛋白H3-赖氨酸（K）9甲基化。然而，PGR和Erα基因的沉默与H3-K27甲基化而不是DNA甲基化的关系更密切。与组蛋白状态的改变一致，G9 a和EZH 2在HCC中的表达高于非癌肝组织（P < 0.01）。这些数据表明，多表观遗传学因素可能与肝癌的发生有关。 ...更多信息接下来，我们研究了2种不同的H3 K9 HMT，SUV 39 H1和G9 a的基于RNAi的抑制（敲低，KD）。在PC 3癌细胞系中敲除两种HMT显著抑制细胞生长，并引起端粒酶活性丧失和端粒缩短的深刻形态学变化。SUV 39 H1 KD细胞显示G2/M分数显著增加。核型分析表明，这是由于与亲本PC 3相比，G9 a KD细胞中染色体数量增加。有趣的是，我们在G9 a KD细胞中发现了异常的中心体形态和数量，而在对照细胞中中心体形态正常。这些数据表明，需要2种HMT，SUV 39 H1和G9 a来维持恶性表型。此外，G9 a可能通过染色质结构而不是通过影响癌细胞中的基因表达来调节中心体复制。靶向这些组蛋白甲基转移酶可能对癌症有治疗益处