Zhou Yi, Chang Renxu, Ji Weiwei, Wang Na, Qi Meiyan, Xu Yi, Guo Jingyu, Zhan Lixing
From the Key Laboratory of Nutrition and Metabolism, Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
From the Key Laboratory of Nutrition and Metabolism, Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
J Biol Chem. 2016 Jan 1;291(1):291-302. doi: 10.1074/jbc.M115.693853. Epub 2015 Nov 2.
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.
癌细胞对各种治疗药物和分子靶点产生耐药性是当前癌症研究面临的一个主要问题。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；该基因座的缺失会破坏细胞极性、抑制细胞凋亡并介导癌症进程。然而，Scribble在耐药性中的作用仍然未知。我们在此表明，敲低Scribble可通过允许Snail积累来增强耐药性，Snail在上皮-间质转化过程中作为转录因子发挥作用。然后，Scribble的缺失通过促进HuR从细胞核向细胞质的转位来激活mRNA结合蛋白人类抗原R（HuR）。此外，我们证明HuR可以识别编码Snail的mRNA的富含AU元件，从而调节Snail的翻译。此外，Scribble缺失诱导的HuR转位通过激活p38丝裂原活化蛋白激酶（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，它直接参与发育转录因子Snail的调控，并提示了Scribble介导癌症耐药性的机制。
