Upregulation of KLF4 by Methylseleninic Acid in Human Esophageal Squamous Cell Carcinoma Cells: Modification of Histone H3 Acetylation Through HAT/HDAC Interplay
Upregulation of KLF4 by Methylseleninic Acid in Human Esophageal Squamous Cell Carcinoma Cells: Modification of Histone H3 Acetylation Through HAT/HDAC Interplay
复制标题
DOI：
10.1002/mc.22174
复制
发表时间：
2015-10-01
影响因子：
4.6
通讯作者：
Xu, Ningzhi
中科院分区：
文献类型：
--
作者：
Hu, Chenfei;Liu, Mei;Xu, Ningzhi
食管鳞状细胞癌（ESCC）在中国某些地区发病率很高。在中国临夏进行的一项研究表明，补充含硒化合物与显著降低癌症死亡率有关。因此，硒可能是一种潜在的抗食管癌药物。在本研究中，甲基硒酸（MSA）在体外和体内均能抑制ESCC细胞的生长。经MSA处理后，ESCC细胞中组蛋白去乙酰化酶（hdac）活性降低，一般控制非抑制蛋白5 （GCN5）上调。同时，检测到H3K9乙酰化（H3K9ac）显著升高。MSA处理后，kruppel-like factor 4 （KLF4）也出现上调。此外，染色质免疫沉淀（ChIP）实验显示，MSA处理后，乙酰化组蛋白H3更多地位于KLF4启动子区域。此外，GCN5的敲低降低了H3K9ac和KLF4的蛋白水平，同时减少了细胞生长抑制。综上所述，我们的结果表明，MSA可以抑制ESCC细胞的生长，至少部分是通过MSA- hdac /GCN5-H3K9ac-KLF4轴。据我们所知，这是第一次报道MSA诱导组蛋白H3在Lys9位点乙酰化，这可能取决于hdac和HATs之间的活性和平衡。(C) 2014 Wiley期刊公司
Esophageal squamous cell carcinoma (ESCC) occurs at a very high frequency in certain areas of China. Supplementation with selenium-containing compounds was associated with a significantly lower cancer mortality rate in a study conducted in Linxia, China. Thus, selenium could be a potential anti-esophageal cancer agent. In this study, methylseleninic acid (MSA) could inhibit cell growth of ESCC cells in vitro and in vivo. Upon treated with MSA, the activity of histone deacetylases (HDACs) was decreased and general control nonrepressed protein 5 (GCN5) was upregulated in ESCC cells. Meanwhile, a significant increase of H3K9 acetylation (H3K9ac) was detected. Upregulation of kruppel-like factor 4 (KLF4) was also observed after MSA treatment. Additionally, the acetylated histone H3 located more at KLF4 promoter region after MSA treatment, shown by chromatin immunoprecipitation (ChIP) assay. Moreover, knockdown of GCN5 decreased the protein level of both H3K9ac and KLF4, along with less cell growth inhibition. Taken all, our results indicated that MSA could inhibit ESCC cell growth, at least in part, by MSA-HDAC/GCN5-H3K9ac-KLF4 axis. To our best knowledge, this is the first report that MSA induced acetylation of histone H3 at Lys9, which might depend on the activities and the balance between HDACs and HATs. (C) 2014 Wiley Periodicals, Inc.