Aldehyde dehydrogenase 1A1 stabilizes transcription factor Gli2 and enhances the activity of Hedgehog signaling in hepatocellular cancer
Aldehyde dehydrogenase 1A1 stabilizes transcription factor Gli2 and enhances the activity of Hedgehog signaling in hepatocellular cancer
复制标题
乙醛脱氢酶 1A1 稳定转录因子 Gli2 并增强肝细胞癌中 Hedgehog 信号传导的活性
DOI：
10.1016/j.bbrc.2016.02.052
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发表时间：
2016
影响因子：
3.1
通讯作者：
Xu Linlin
中科院分区：
文献类型：
--
作者：
Yan Zhengwei;Xu Liyao;Zhang Junyan;Lu Quqin;Luo Shiwen;Xu Linlin
Gli转录因子是介导Hedgehog（Hh）信号传导激活的主要转录调节因子。近年来的研究表明，Gli蛋白在转录和转录后也受到非经典机制的调控，不依赖于Hh信号，但其确切的调控机制尚不清楚。利用差示质谱法，我们发现醛脱氢酶1A 1（ALDH 1A 1）与转录因子Gli 2相关。ALDH 1A 1的过表达增加了Gli 2蛋白水平;相反，ALDH 1A 1的缺失促进了Gli 2的降解。此外，ALDH 1A 1的异位表达对Gli 2的mRNA表达没有影响，表明ALDH 1A 1在Gli 2的稳定性中起作用。进一步的研究表明，ALDH 1A 1以非催化的方式延长了Gli 2蛋白的稳定性。最后，我们发现ALDH 1A 1的过表达激活了Hh信号通路，促进了肝癌细胞的生长、迁移和侵袭。总之，这些结果阐明了ALDH 1A 1在Hh信号通路激活中的调节作用，并强调了肝细胞癌细胞中Hh信号通路异常激活的新机制
The Gli transcription factors are primary transcriptional regulators that mediate the activation of Hedgehog (Hh) signaling. Recent studies have revealed that Gli proteins are also regulated transcriptionally and post-translationally through noncanonical mechanisms, independent of Hh signaling.However, the precise mechanisms involved in the regulation of Gli proteins remain unclear. Using a differential mass-spectrometry approach, we found that aldehyde dehydrogenase 1A1 (ALDH1A1) is associated with transcription factor Gli2. Overexpression of ALDH1A1 increased Gli2 protein levels; in contrast, ALDH1A1 depletion facilitated Gli2 degradation. In addition, Gli2 mRNA expression was not affected by ectopic expression of ALDH1A1, indicating the role of ALDH1A1 in the stabilization of Gli2.Further investigation showed that ALDH1A1 prolonged the stability of Gli2 protein in a catalyticindependent manner. Finally, we showed that overexpression of ALDH1A1 activated the Hh signaling pathway and promoted cell growth, migration and invasion in hepatocellular cancer cells. Together, these results illustrate regulatory roles of ALDH1A1 in the activation of the Hh signaling pathway and highlight a novel mechanism for the aberrant activation of the Hh signaling pathway in hepatocellular cancer cells