Comparative Oncology Laboratory, University of California Davis, Davis, California, United States of America.
PLoS One. 2014 Jan 3;9(1):e84015. doi: 10.1371/journal.pone.0084015. eCollection 2014.
P73, a member of the p53 family, plays a critical role in neural development and tumorigenesis. Due to the usage of two different promoters, p73 is expressed as two major isoforms, TAp73 and ΔNp73, often with opposing functions. Here, we reported that transcriptional factor DEC1, a target of the p53 family, exerts a distinct control of TAp73 and ΔNp73 expression. In particular, we showed that DEC1 was able to increase TAp73 expression via transcriptional activation of the TAp73 promoter. By contrast, Np73 transcription was inhibited by DEC1 via transcriptional repression of the ΔNp73 promoter. To further explore the underlying mechanism, we showed that DEC1 was unable to increase TAp73 expression in the absence of HDAC8, suggesting that HDAC8 is required for DEC1 to enhance TAp73 expression. Furthermore, we found that DEC1 was able to interact with HDAC8 and recruit HDAC8 to the TAp73, but not the ΔNp73, promoter. Together, our data provide evidence that DEC1 and HDAC8 in differentially regulate TAp73 and ΔNp73 expression, suggesting that this regulation may lay a foundation for a therapeutic strategy to enhance the chemosensitivity of tumor cells.
P73 是 p53 家族的一员，在神经发育和肿瘤发生中起着关键作用。由于使用了两个不同的启动子，p73 表达为两种主要的异构体，TAp73 和 ΔNp73，通常具有相反的功能。在这里，我们报道了转录因子 DEC1 是 p53 家族的一个靶标，对 TAp73 和 ΔNp73 的表达有明显的控制作用。特别是，我们表明 DEC1 能够通过 TAp73 启动子的转录激活来增加 TAp73 的表达。相比之下，DEC1 通过 ΔNp73 启动子的转录抑制来抑制 Np73 的转录。为了进一步探讨潜在的机制，我们表明 DEC1 不能在没有 HDAC8 的情况下增加 TAp73 的表达，这表明 HDAC8 是 DEC1 增强 TAp73 表达所必需的。此外，我们发现 DEC1 能够与 HDAC8 相互作用，并将 HDAC8 募集到 TAp73 启动子，但不能募集到 ΔNp73 启动子。总之，我们的数据提供了证据表明 DEC1 和 HDAC8 以不同的方式调节 TAp73 和 ΔNp73 的表达，这表明这种调节可能为增强肿瘤细胞的化疗敏感性奠定了基础。
