FBXO28 targets SNAI1 for ubiquitin-proteasomal degradation in non-small cell lung cancer
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siRNA Screening to Identify Ubiquitin and Ubiquitin-like System Regulators of Biological Pathways in Cultured Mammalian Cells
Published on: May 24, 2014
Jingyu Lin1, Xinran Qiao1, Hua Liu2
1Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Abstract:
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.
Insights
FBXO28 suppresses non-small cell lung cancer (NSCLC) metastasis by targeting SNAI1 for degradation. Lower FBXO28 levels correlate with better NSCLC patient prognosis, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- SNAI1 is a key regulator of epithelial-mesenchymal transition (EMT), crucial for cancer metastasis.
- SNAI1 is degraded by the ubiquitin-proteasome system, but the E3 ligases involved are not fully understood.
- Non-small cell lung cancer (NSCLC) metastasis remains a major challenge in cancer treatment.
Purpose of the Study:
- To investigate the role of FBXO28 in regulating SNAI1 stability and its impact on NSCLC progression.
- To elucidate the mechanism by which FBXO28 affects SNAI1 degradation.
- To explore the therapeutic potential of targeting the FBXO28-SNAI1 axis in NSCLC.
Main Methods:
- Western blotting and immunoprecipitation to assess protein interactions and stability.
- Ubiquitination assays to detect polyubiquitination of SNAI1.
- Cellular assays (migration, invasion) and xenograft models (mice, zebrafish) to evaluate functional roles.
- Pharmacological inhibition of proteasome and GSK3β.
Main Results:
- FBXO28 expression is downregulated in NSCLC tissues and correlates with favorable prognosis.
- FBXO28 directly interacts with SNAI1, promoting its polyubiquitination and degradation via the ubiquitin-proteasome system.
- FBXO28 suppresses NSCLC cell migration and invasion, an effect dependent on SNAI1 and GSK3β phosphorylation.
- FBXO28's regulatory role in metastasis was confirmed in vivo models.
Conclusions:
- FBXO28 acts as a tumor suppressor in NSCLC by destabilizing SNAI1 through the ubiquitin-proteasome pathway.
- The FBXO28-SNAI1 interaction, modulated by GSK3β, represents a novel mechanism controlling EMT and metastasis.
- Targeting FBXO28 or its pathway may offer a promising therapeutic strategy for inhibiting NSCLC metastasis.
