Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells.
Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells.
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DOI：
10.1371/journal.pone.0002037
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发表时间：
2008-04-30
期刊：
影响因子：
3.7
通讯作者：
Issa JP
中科院分区：
文献类型：
--
作者：
Kondo Y;Shen L;Ahmed S;Boumber Y;Sekido Y;Haddad BR;Issa JP
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。癌细胞的特征在于显著的表观遗传失调，包括组蛋白修饰。然而，组蛋白甲基转移酶（HMT）在癌症中的功能作用仍不清楚。我们研究了2种不同H3 K9 HMT，SUV 39 H1和G9 a的基于RNAi的抑制（敲低，KD）。敲除PC 3细胞中的2个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。与对照的FACS分析相比，G9 a KD细胞显示出增加的DNA含量（在2个独立克隆中为1.7倍）。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（从61至102）。有趣的是，我们发现异常的中心体形态和数量在约25%的G9 a KD细胞，而中心体形态正常的对照细胞。在SUV 39 H1或G9 a KD后的微阵列分析显示，在39，000个基因中很少有基因上调。在KD细胞中，沉默的抑癌基因p16和RASSF 1A没有被激活。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在癌症中具有治疗益处。
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. However, the functional roles of the histone methyltransferases (HMT) in cancer remain unclear. We studied RNAi-based inhibition (knockdown, KD) of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the 2 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. G9a KD cells showed increased DNA content (1.7-fold in 2 independent clones) compared with FACS analyses to control. Karyotype analyses showed that this was due to an increased number of chromosomes (from 61 to 102) in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in about 25% of the G9a KD cells, while centrosomes were morphologically normal in control cells. Microarray analyses after KD of SUV39H1 or G9a showed very few genes up-regulated among the 39,000 genes. The silenced tumor-suppressor genes p16 and RASSF1A were not activated in KD 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.
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影响因子：
4.2
作者：
Kondo, Yutaka;Shen, Lanlan;Sekido, Yoshitaka
通讯作者：
Sekido, Yoshitaka
影响因子：
2.7
作者：
Colella, S;Shen, L;Krahe, R
通讯作者：
Krahe, R
影响因子：
10.5
作者：
Tachibana, M;Sugimoto, K;Shinkai, Y
通讯作者：
Shinkai, Y
影响因子：
19
作者：
Gilson, Eric;Laroche, Thierry;Gasser, Susan M.
通讯作者：
Gasser, Susan M.
影响因子：
14.9
作者：
CLARK, SJ;HARRISON, J;FROMMER, M
通讯作者：
FROMMER, M