Roles of Histone Methyltransferase in Human Cancer

组蛋白氨基末端尾部的修饰影响调控因子和复合物进入染色质，从而影响生物过程。肿瘤细胞的特征是显著的表观遗传失调，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。首先，我们研究了肝细胞癌（HCC）中组蛋白修饰变化和DNA甲基化。在所有HCC中都经常检测到异常的DNA甲基化。肝癌细胞系的表观遗传状态显示P16和RASSF1a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甲基化的关系更密切，而与DNA甲基化的关系更密切。与组蛋白状态的改变一致，肝癌组织中G9a和EZH2的表达高于非癌性肝组织（P < 0.01），这些数据表明肝癌细胞中存在多种表观基因的沉默机制。接下来，我们研究了基于rnai的2种不同H3K9 hmt， SUV39H1和G9a的抑制（敲低，KD）。在PC3癌细胞系中，敲低这两种hmt可显著抑制细胞生长，引起端粒酶活性降低、端粒缩短等形态学改变。SUV39H1 KD细胞G2/M比例显著升高。核型分析表明，这是由于与亲本PC3相比，G9a KD细胞中的染色体数量增加。有趣的是，我们在G9a 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，2个hmt、SUV39H1和G9a是恶性表型延续所必需的。此外，G9a在调节中心体复制中发挥关键作用，可能是通过染色质结构而不是通过影响癌细胞中的基因表达。靶向这些组蛋白甲基转移酶可能对癌症有治疗益处

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