FBXO31 Suppresses Gastric Cancer EMT by Targeting Snail1 for Proteasomal Degradation

The F-box protein FBXO31, a component of the Skp1/Cul1/F-box (SCF) E3 ubiquitin ligase complex, plays an important regulatory role in neuronal development, stress response, and tumorigenesis. Our recent report indicates that FBXO31 functions as a tumor suppressor in gastric cancer, and the loss of FBXO31 protein is associated with a higher malignant phenotype and poorer prognosis. However, little is known about the underlying mechanism. In this study, FBXO31 inhibits gastric cancer progression by suppressing the epithelial-mesenchymal transition (EMT). FBXO31 overexpression decreases, whereas its inhibition increases, the protein level of the EMT transcription factor Snail1 (SNAI1), respectively. Further evidence demonstrates that FBXO31 interacts with Snail1 and mediates the ubiquitin- and proteasome-dependent degradation of Snail1 in gastric cancer. The F-box domain of FBXO31 and the phosphorylation of Snail1 are necessary for the molecular interaction between FBXO31 and Snail1. Mouse modeling experiments reveal that FBXO31 overexpression inhibits in vivo colonization of gastric cancer cells. Furthermore, a highly significant negative correlation between FBXO31 and Snail1 is validated in human gastric cancer clinical specimens. Taken together, these findings identify Snail1 as a new target protein of FBXO31 in gastric cancer and substantiate a novel regulatory role of FBXO31 on gastric cancer progression and metastasis.Implication: These findings demonstrate that FBXO31 exerts the tumor-inhibitory role in gastric cancer by ubiquitin-mediated degradation of Snail1, which represents a viable strategy of FBXO31 activators in the prevention and therapy of gastric cancer. Mol Cancer Res; 16(2); 286-95. ©2017 AACR.