FBXO28 targets SNAI1 for ubiquitin-proteasomal degradation in non-small cell lung cancer.

SNAI1 is a central regulator of the epithelial-mesenchymal transition, which is highly unstable and degraded through the ubiquitin-proteasome system. Although a panel of E3 ubiquitin ligases responsible for SNAI1 degradation have been discovered, whether there exists other E3 ubiquitin ligase remains unclarified. In this study, we demonstrate that FBXO28 expression is downregulated in non-small cell lung cancer (NSCLC) tissues compared to adjacent non-cancerous tissues, correlating with beneficial patient prognosis. Specifically, FBXO28 physically interacts with SNAI1, promoting its polyubiquitination and degradation in a mechanism dependent on phosphorylation by glycogen synthase kinase-3β (GSK3β). Functional assays indicate that FBXO28 controls the half-life of SNAI1 protein, which are abrogated by proteasome inhibitor MG132 in NSCLC cells. Importantly, FBXO28 suppresses the migratory and invasive abilities of NSCLC cells, an effect that can be mitigated by GSK3β inhibition. We also present data to show that SNAI1, along with SNAI2, mediates the regulatory function of FBXO28 toward migration and invasion of NSCLC cells in mice and zebrafish xenograft models. Collectively, our findings elucidate a significant role for FBXO28 in regulating SNAI1 stability via the ubiquitin-proteasome system, thereby providing insights into therapeutic strategies aimed at constraining metastasis in NSCLC.