The transcription factor ZBP-89 suppresses p16 expression through a histone modification mechanism to affect cell senescence
The transcription factor ZBP-89 suppresses p16 expression through a histone modification mechanism to affect cell senescence
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转录因子ZBP-89通过组蛋白修饰机制抑制p16表达影响细胞衰老
DOI：
10.1111/j.1742-4658.2009.07128.x
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发表时间：
2009-08-01
期刊：
影响因子：
5.4
通讯作者：
Lu, Jun
中科院分区：
文献类型：
--
作者：
Feng, Yunpeng;Wang, Xiuli;Lu, Jun
转录因子ZBP-89与生长停滞和凋亡的诱导有关。在这篇文章中，我们证明ZBP-89能够抑制NCI-H460人肺癌细胞的衰老，通过表观遗传学调节p16（INK 4a）的表达。具体而言，我们的研究结果表明，ZBP-89的敲低RNA干扰刺激细胞衰老NCI-H460细胞，判断衰老相关的β-半乳糖苷酶活性测定和衰老相关的异染色质病灶测定，这一过程可以逆转RNA干扰介导的p16（INK 4a）沉默。我们还表明，组蛋白脱乙酰酶（HDAC）3和HDAC 4抑制p16（INK 4a）启动子活性的剂量依赖性方式。此外，染色质免疫沉淀试验证实，HDAC 3通过涉及组蛋白乙酰化修饰的表观遗传机制被ZBP-89募集到p16（INK 4a）启动子。此外，免疫荧光和免疫共沉淀试验显示ZBP-89和HDAC 3形成复合物。这些数据表明，ZBP-89和HDAC 3，而不是HDAC 4，可以协同工作，通过下调p16（INK 4a）的表达，通过组蛋白的表观遗传修饰来抑制细胞衰老。
The transcription factor ZBP-89 has been implicated in the induction of growth arrest and apoptosis. In this article, we demonstrate that ZBP-89 was able to restrain senescence in NCI-H460 human lung cancer cells, through epigenetically regulating p16(INK4a) expression. Specifically, our results indicate that knockdown of ZBP-89 by RNA interference stimulated cellular senescence in NCI-H460 cells, as judged by the senescence-associated beta-galactosidase activity assay and senescence-associated heterochromatin foci assay, and this process could be reversed by RNA interference-mediated p16(INK4a) silencing. We also show that histone deacetylase (HDAC) 3 and HDAC4 inhibited p16(INK4a) promoter activity in a dose-dependent manner. Furthermore, chromatin immunoprecipitation assays verified that HDAC3 was recruited to the p16(INK4a) promoter by ZBP-89 through an epigenetic mechanism involving histone acetylation modification. Moreover, immunofluorescence and coimmunoprecipitation assays revealed that ZBP-89 and HDAC3 formed a complex. These data suggest that ZBP-89 and HDAC3, but not HDAC4, can work coordinately to restrain cell senescence by downregulating p16(INK4a) expression through an epigenetic modification of histones.