Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756, Republic of Korea.
Biochem Biophys Res Commun. 2013 Aug 23;438(2):445-51. doi: 10.1016/j.bbrc.2013.07.099. Epub 2013 Jul 31.
PUMA is a crucial regulator of apoptotic cell death mediated by p53-dependent and p53-independent mechanisms. In many cancer cells, PUMA expression is induced in response to DNA-damaging reagent in a p53-dependent manner. However, few studies have investigated transcription factors that lead to the induction of PUMA expression via p53-independent apoptotic signaling. In this study, we found that the transcription factor Sox4 increased PUMA expression in response to trichostatin A (TSA), a histone deacetylase inhibitor in the p53-null human lung cancer cell line H1299. Ectopic expression of Sox4 led to the induction of PUMA expression at the mRNA and protein levels, and TSA-mediated up-regulation of PUMA transcription was repressed by the knockdown of Sox4. Using luciferase assays and chromatin immunoprecipitation, we also determined that Sox4 recruits p300 on the PUMA promoter region and increases PUMA gene expression in response to TSA treatment. Taken together, these results suggest that Sox4 is required for p53-independent apoptotic cell death mediated by PUMA induction via TSA treatment.
PUMA 是由 p53 依赖性和非依赖性机制介导的凋亡细胞死亡的关键调节因子。在许多癌细胞中，PUMA 的表达是在 p53 依赖性方式下响应 DNA 损伤试剂而被诱导的。然而，很少有研究调查转录因子，这些转录因子通过非 p53 依赖性凋亡信号导致 PUMA 的表达诱导。在这项研究中，我们发现转录因子 Sox4 在 p53 缺失的人肺癌细胞系 H1299 中响应组蛋白去乙酰化酶抑制剂曲古抑菌素 A（TSA）时增加了 PUMA 的表达。Sox4 的异位表达导致在 mRNA 和蛋白质水平上诱导了 PUMA 的表达，并且 Sox4 的敲低抑制了 TSA 介导的 PUMA 转录的上调。通过荧光素酶测定和染色质免疫沉淀，我们还确定 Sox4 将 p300 募集到 PUMA 启动子区域，并响应 TSA 处理增加 PUMA 基因表达。总之，这些结果表明 Sox4 是通过 TSA 处理诱导 PUMA 诱导的非 p53 依赖性凋亡细胞死亡所必需的。
