Oncotarget

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This article has been corrected. Correction in: Oncotarget. 2019; 10:5888-5888.

Atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 controls the core epithelial-to-mesenchymal transition-inducing transcription factors

Ming Xu, Changhong Zhu, Xian Zhao, Cheng Chen, Hailong Zhang, Haihua Yuan, Rong Deng, Jinzhuo Dou, Yanli Wang, Jian Huang, Qin Chen, Bin Jiang and Jianxiu Yu _

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Oncotarget. 2015; 6:979-994. https://doi.org/10.18632/oncotarget.2825

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Abstract

Ming Xu1,2, Changhong Zhu2, Xian Zhao2, Cheng Chen2, Hailong Zhang2, Haihua Yuan1, Rong Deng2, Jinzhuo Dou2, Yanli Wang2, Jian Huang2, Qin Chen2, Bin Jiang1 and Jianxiu Yu2,3

1 Institute of Oncology & Department of Oncology, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2 Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China

3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Correspondence:

Jianxiu Yu, email:

Keywords: Epithelial-mesenchymal transition (EMT), EMT-Inducing Transcription Factors (EMT-TFs), Fbxo45; miR-27a*, ubiquitin degradation

Received: August 05, 2014 Accepted: November 24, 2014 Published: November 25, 2014

Abstract

Epithelial-mesenchymal transition (EMT) plays a critical role in the development of tumor metastases by enhancing migration/invasion. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. The K48-linkaged ubiquitination capability on Zeb2 relies on its functional SBD domain. In addition, miR-27a* can directly down-regulate the expression of Fbxo45, preventing degradation of EMT-TFs and thus ensuring EMT phenotype. We suggest that Fbxo45 is a key node of the miR-27a*/Fbxo45/EMT-TFs signaling axis.


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