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

// Ming Xu 1,2 , Changhong Zhu 2 , Xian Zhao 2 , Cheng Chen 2 , Hailong Zhang 2 , Haihua Yuan 1 , Rong Deng 2 , Jinzhuo Dou 2 , Yanli Wang 2 , Jian Huang 2 , Qin Chen 2 , Bin Jiang 1 and Jianxiu Yu 2,3 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 (SPF Fbxo45 ) 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.