Loss of Scribble Promotes Snail Translation through Translocation of HuR and Enhances Cancer Drug Resistance.
Loss of Scribble Promotes Snail Translation through Translocation of HuR and Enhances Cancer Drug Resistance.
复制标题
失去 Scribble 可通过 HuR 易位促进蜗牛翻译并增强癌症耐药性。
DOI：
10.1074/jbc.m115.693853
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发表时间：
2016-01-01
期刊：
影响因子：
--
通讯作者：
Zhan L
中科院分区：
文献类型：
--
作者：
Zhou Y;Chang R;Ji W;Wang N;Qi M;Xu Y;Guo J;Zhan L
癌细胞对各种治疗药物和分子靶点的耐药性是当前癌症研究面临的主要问题。肿瘤抑制基因 Scribble 编码一种在果蝇和哺乳动物之间保守的极性蛋白；该位点的丢失会破坏细胞极性，抑制细胞凋亡，并介导癌症过程。然而，Scribble 在耐药性中的作用仍然未知。我们在这里表明，Scribble 的敲低通过允许 Snail 的积累来增强耐药性，Snail 在上皮间质转化过程中充当转录因子。然后，Scribble 的缺失会促进 mRNA 结合蛋白人类抗原 R (HuR) 从细胞核易位到细胞质，从而激活该蛋白。此外，我们证明 HuR 可以识别 Snail 编码 mRNA 中富含 AU 的元件，从而调节 Snail 翻译。此外，Scribble 诱导的 HuR 易位丧失通过激活 p38 MAPK 途径介导 Snail 的积累。因此，这项工作阐明了极性蛋白 Scribble 的作用，该蛋白直接参与发育转录因子 Snail 的调节，并提出了 Scribble 介导癌症耐药性的机制。
Drug resistance of cancer cells to various therapeutic agents and molecular targets is a major problem facing current cancer research. The tumor suppressor gene Scribble encodes a polarity protein that is conserved between Drosophila and mammals; loss of the locus disrupts cell polarity, inhibits apoptosis, and mediates cancer process. However, the role of Scribble in drug resistance remains unknown. We show here that knockdown of Scribble enhances drug resistance by permitting accumulation of Snail, which functions as a transcription factor during the epithelial-mesenchymal transition. Then, loss of Scribble activates the mRNA-binding protein human antigen R (HuR) by facilitating translocation of HuR from the nucleus to the cytoplasm. Furthermore, we demonstrate HuR can recognize AU-rich elements of the Snail-encoding mRNA, thereby regulating Snail translation. Moreover, loss of Scribble-induced HuR translocation mediates the accumulation of Snail via activation of the p38 MAPK pathway. Thus, this work clarifies the role of polarity protein Scribble, which is directly implicated in the regulation of developmental transcription factor Snail, and suggesting a mechanism for Scribble mediating cancer drug resistance.