Loss of Scribble Promotes Snail Translation through Translocation of HuR and Enhances Cancer Drug Resistance.
Bottom Line: 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.
Affiliation: 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.Show MeSH
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Mentions: To investigate the cellular effects of Scribble in epithelial cells, we established cell lines stably expressing Scribble shRNA and developed a three-dimensional culture model (22). Surprisingly, when propagated in this three-dimensional culture system, Scribble KD cells exhibited an enhanced ability to invade through Matrigel-impregnated membranes, and disrupted three-dimensional acinar structures generated in a non-small lung cancer cell (NSLCC) line (CRL-1848) and HeLa cells (Fig. 2A). However, Scribble KD lines did not exhibit apparent morphological differences compared with control cells when grown in two-dimensional cultures (data not shown). Despite an apparent lack of morphological effect, Scribble KD lines showed changes in E-cadherin and N-cadherin protein levels in a two-dimensional culture (Fig. 2B), with Scribble KD lines exhibiting a mesenchymal phenotype for production of these two cadherins production, a signature that serves as a marker of EMT fate.
Affiliation: 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.