title: Loss of Scribble Promotes Snail Translation through Translocation of HuR and Enhances Cancer Drug Resistance.
abstract: 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.
authors.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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.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.
authors.forename: Renxu
authors.initials: R
authors.lastname: Chang
authors.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.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Ji
authors.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.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.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.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Qi
authors.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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.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.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Guo
authors.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 lxzhan@sibs.ac.cn.
authors.forename: Lixing
authors.initials: L
authors.lastname: Zhan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011132:Polyribosomes / Q000187:drug effects / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; C480591:SCRIB protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C000604451:sna protein, Drosophila; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin
keywords: HuR; Scribble; Snail; apoptosis; cancer biology; cancer therapy; cell polarity; cisplatin; drug resistance