Wnt-induced deubiquitination FoxM1 ensures nucleus β-catenin transactivation

Area of Science:

• Molecular Biology
• Cellular Signaling
• Cancer Biology

Background:

• Canonical Wnt signaling is crucial for development and disease.
• The precise mechanisms of β-catenin recruitment to target gene promoters remain incompletely understood.
• Understanding Wnt signaling regulation is vital for therapeutic development.

Purpose of the Study:

• To elucidate the role of FoxM1 in Wnt signaling activation.
• To identify novel regulatory mechanisms controlling β-catenin/TCF4 transactivation.
• To explore the therapeutic potential of targeting the Wnt pathway.

Main Methods:

• Identification of FoxM1 as a Wnt signaling target.
• Investigation of GSK3-mediated phosphorylation and FBXW7-mediated ubiquitination of FoxM1.
• Analysis of the interaction between FoxM1 and USP5 in response to Wnt activation.
• Assessment of FoxM1's role in β-catenin recruitment and Wnt target gene expression.

Main Results:

• FoxM1 is a novel Wnt signaling target, essential for β-catenin/TCF4 transactivation.
• GSK3-mediated phosphorylation of FoxM1 at serine 474 targets it for FBXW7-mediated ubiquitination and degradation.
• Wnt signaling activation inhibits FoxM1 phosphorylation, promoting its interaction with USP5 for deubiquitination and stabilization.
• Stabilized FoxM1 facilitates β-catenin recruitment to Wnt target gene promoters, overcoming ICAT inhibition and driving Wnt signaling.

Conclusions:

• Wnt-induced deubiquitination of FoxM1 is a critical regulatory mechanism for canonical Wnt signaling.
• The USP5-FoxM1 axis plays a key role in Wnt-mediated cell proliferation.
• Targeting FoxM1 deubiquitination may offer a novel therapeutic strategy for Wnt-dependent cancers.