F-box protein FBXO16 functions as a tumor suppressor by attenuating nuclear β-catenin function

Area of Science:

• Molecular Biology
• Oncology
• Cell Biology

Background:

• Aberrant activation of β-catenin signaling is a hallmark of various human diseases, particularly cancer.
• The precise regulatory mechanisms governing active Wnt/β-catenin pathways remain incompletely understood.
• Understanding these pathways is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To investigate the role of F-box protein 16 (FBXO16) in the regulation of Wnt/β-catenin signaling.
• To determine if FBXO16 functions as a tumor suppressor by modulating β-catenin levels.
• To explore the therapeutic potential of targeting the FBXO16-β-catenin interaction in cancer.

Main Methods:

• Investigated the interaction between FBXO16 and nuclear β-catenin.
• Assessed the effect of FBXO16 on β-catenin polyubiquitination and proteasomal degradation.
• Utilized cell-based assays to evaluate the impact of FBXO16 depletion on cancer cell invasion, growth, and epithelial-to-mesenchymal transition (EMT).
• Analyzed the correlation between FBXO16 and β-catenin expression in clinical breast cancer samples.

Main Results:

• FBXO16, a component of the SCF (SKP1-Cullin1-F-box protein) complex, physically interacts with the C-terminal domain of β-catenin.
• FBXO16 promotes lysine 48-linked polyubiquitination of β-catenin, targeting it for proteasomal degradation.
• Depletion of FBXO16 leads to elevated nuclear β-catenin levels, enhancing cancer cell invasion, tumor growth, and EMT.
• An inverse correlation between FBXO16 and β-catenin expression was observed in clinical breast cancer samples.

Conclusions:

• FBXO16 functions as a putative tumor suppressor by facilitating the degradation of nuclear β-catenin via the SCF^FBXO16 complex.
• FBXO16 inhibits cancer progression and EMT by maintaining low β-catenin levels.
• This study identifies FBXO16 as a novel therapeutic target for cancers driven by aberrant β-catenin activation.