Wang Xiuli, Feng Yunpeng, Xu Liang, Chen Yuli, Zhang Yu, Su Dongmei, Ren Guoling, Lu Jun, Huang Baiqu
Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, P.R. China.
Biochim Biophys Acta. 2008 Oct;1783(10):1876-83. doi: 10.1016/j.bbamcr.2008.05.015. Epub 2008 Jun 17.
The transcription factor YY1 has been implicated to play a role in cell growth control. In this report, we demonstrate that YY1 was able to suppress NCI-H460 cell senescence through regulating the expression of p16(INK4a), a cyclin-dependent kinase inhibitor. We also show that YY1 participated in the repression of p16(INK4a) expression in 293T cells through an epigenetic mechanism involving histone acetylation modification. Specifically, HDAC3 and HDAC4 inhibited the p16(INK4a) promoter activity. The chromatin immunoprecipitation (ChIP) assays verified that HDAC3 and HDAC4 were recruited to p16(INK4a) promoter by YY1. Moreover, co-immunoprecipitation assays revealed that these three protein factors formed a complex. Furthermore, knockdown of these factors induced cell enlargement and flattened morphology and significantly increased the SA-beta-gal activity, a biochemical marker of cell senescence. Overall, data from this study suggest that YY1, HDAC3 and HDAC4 restrained cell senescence by repressing p16(INK4a) expression through an epigenetic modification of histones.
转录因子YY1被认为在细胞生长控制中发挥作用。在本报告中，我们证明YY1能够通过调节细胞周期蛋白依赖性激酶抑制剂p16(INK4a)的表达来抑制NCI-H460细胞衰老。我们还表明，YY1通过涉及组蛋白乙酰化修饰的表观遗传机制参与了293T细胞中p16(INK4a)表达的抑制。具体而言，HDAC3和HDAC4抑制了p16(INK4a)启动子活性。染色质免疫沉淀(ChIP)分析证实，HDAC3和HDAC4被YY1招募到p16(INK4a)启动子上。此外，免疫共沉淀分析表明这三种蛋白质因子形成了一个复合物。此外，敲低这些因子会导致细胞增大和平坦化形态，并显著增加SA-β-半乳糖苷酶活性，这是细胞衰老的一个生化标志物。总体而言，本研究数据表明，YY1、HDAC3和HDAC4通过组蛋白的表观遗传修饰抑制p16(INK4a)表达来抑制细胞衰老。
