Loss of Histone Deacetylase 4 Causes Segregation Defects during Mitosis of p53-Deficient Human Tumor Cells
Loss of Histone Deacetylase 4 Causes Segregation Defects during Mitosis of p53-Deficient Human Tumor Cells
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DOI：
10.1158/0008-5472.can-08-2796
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发表时间：
2009-08-01
期刊：
影响因子：
11.2
通讯作者：
Filocamo, Gessica
中科院分区：
文献类型：
--
作者：
Cadot, Bruno;Brunetti, Mirko;Filocamo, Gessica
我们使用RNA干扰（RNAi）和敲除细胞研究组蛋白脱乙酰酶4（HDAC 4）的作用，以明确其在肿瘤和正常细胞细胞周期进程中的作用。HDAC 4的消融导致人肿瘤细胞的生长抑制，但在正常人皮肤成纤维细胞（NHDF）或造血祖细胞中没有可检测到的作用。HDAC 4-/+或HDAC 4-/-鼠胚胎成纤维细胞未显示可检测的生长缺陷。另一方面，在HeLa细胞中，HDAC 4 RNAi产生有丝分裂停滞，随后产生半胱天冬酶依赖性凋亡。有丝分裂阻滞的细胞显示染色体分离缺陷。尽管p53野生型和p53缺失肿瘤细胞的生长受到HDAC 4消融的影响，但仅在p53缺失细胞中观察到分离缺陷。HDAC 4与PP 2A-B56调节亚基相关，已知其参与染色体分离，并且PP 2A的结构亚基A或调节亚基B56的RNAi也引起染色体分离缺陷。我们得出结论，HDAC 4是所需的肿瘤细胞的细胞周期进展的多种机制，其中之一似乎是特定的p53缺陷的细胞通过染色体分离缺陷。相反，HDAC 4不是NHDF进展所必需的。因此，我们认为，HDAC 4的表达或功能的系统性选择性干扰，预计有一个显着的治疗窗口，特别是对p53缺陷的肿瘤。[Cancer Res 2009;69（15）：6074-82]
We investigated the role of histone deacetylase 4 (HDAC4) using RNA interference (RNAi) and knockout cells to specifically address its role in cell cycle progression in tumor and normal cells. Ablation of HDAC4 led to growth inhibition in human tumor cells but not to detectable effects in normal human dermal fibroblasts (NHDF) or myclopoietic progenitors. HDAC4-/+ or HDAC4-/- murine embryonic fibroblasts showed no detectable growth defects. On the other hand, HDAC4 RNAi in HeLa cells produced mitotic arrest followed by caspase-dependent apoptosis. Mitotically arrested cells showed chromosome segregation defects. Even though the growth of both p53-wild-type and p53-null tumor cells were affected by HDAC4 ablation, segregation defects were observed only in p53-null cells. HDAC4 associates with the PP2A-B56 regulatory subunit, which is known to be involved in chromosome segregation, and RNAi of either the structural subunit A or the regulatory subunit B56 of PP2A also caused chromosome segregation, defects. We conclude that HDAC4 is required for cell cycle progression of tumor cells by multiple mechanisms, one of which seems to be specific to p53-deficient cells through chromosome segregation defects. On the contrary, HDAC4 is not required for the progression of NHDF. We therefore suggest that systemic selective interference with the expression or function of HDAC4 is expected to have a significant therapeutic window, in particular, for p53-deficient tumors. [Cancer Res 2009;69(15):6074-82]