Regulation of Chk2 gene expression in lymphoid malignancies: involvement of epigenetic mechanisms in Hodgkin's lymphoma cell lines
Regulation of Chk2 gene expression in lymphoid malignancies: involvement of epigenetic mechanisms in Hodgkin's lymphoma cell lines
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DOI：
10.1038/sj.cdd.4401461
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发表时间：
2004-12-01
影响因子：
12.4
通讯作者：
Minami, Y
中科院分区：
文献类型：
--
作者：
Kato, N;Fujimoto, H;Minami, Y
肿瘤抑制因子Chk 2激酶在调节DNA损伤后的细胞周期检查点和细胞凋亡中起着至关重要的作用。我们研究了编码Chk 2和几种细胞周期调节因子的基因在9种淋巴恶性肿瘤细胞系中的表达水平，其中包括3种霍奇金淋巴瘤（HL）细胞系。我们发现，所有HL细胞系表现出Chk 2表达急剧减少，而没有任何明显的Chk 2基因突变。然而，在用组蛋白去乙酰化酶抑制剂阿司他丁A（TsA）和丁酸钠（SB）或用DNA甲基转移酶抑制剂5-氮杂-2 '-脱氧胞苷（5Aza-dC）处理后，HL细胞中Chk 2的表达恢复。染色质免疫沉淀（Chip）分析显示，用TsA、SB或5Aza-dC处理HL细胞导致乙酰化组蛋白H3和H4水平增加，Chk 2启动子处二甲基化H3赖氨酸9水平降低。这些结果表明，Chk 2基因的表达下调HL细胞通过表观遗传机制。
The tumor suppressor Chk2 kinase plays crucial roles in regulating cell-cycle checkpoints and apoptosis following DNA damage. We investigated the expression levels of the genes encoding Chk2 and several cell-cycle regulators in nine cell lines from lymphoid malignancies, including three Hodgkin's lymphoma (HL) lines. We found that all HL cell lines exhibited a drastic reduction in Chk2 expression without any apparent mutation of the Chk2 gene. However, expression of Chk2 in HL cells was restored following treatment with the histone deacetylase inhibitors trichostatin A (TsA) and sodium butyrate (SB), or with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza-dC). Chromatin-immunoprecipitation ( Chip) assays revealed that treatment of HL cells with TsA, SB or 5Aza-dC resulted in increased levels of acetylated histones H3 and H4, and decreased levels of dimethylated H3 lysine 9 at the Chk2 promoter. These results indicate that expression of the Chk2 gene is downregulated in HL cells via epigenetic mechanisms.