Dishevelled-1 DIX and PDZ domain lysine residues regulate oncogenic Wnt signaling

Area of Science:

• Molecular Biology
• Cell Signaling
• Oncology

Background:

• Dishevelled (DVL) proteins are key regulators of the Wnt signaling pathway, mediating signal transmission.
• The precise molecular mechanisms governing DVL-mediated Wnt signal relay remain incompletely understood.
• Post-translational modifications, such as acetylation, are increasingly recognized as critical regulators of protein function.

Purpose of the Study:

• To investigate the functional significance of specific lysine residues on DVL-1 that undergo post-translational acetylation.
• To elucidate how DVL-1 lysine acetylation impacts Wnt signaling, gene expression, and oncogenic functions.
• To explore the potential therapeutic and prognostic implications of these DVL-1 modifications.

Main Methods:

• Site-specific mutagenesis of DVL-1 lysines (K34, K69, K285) to study the effects of acetylation.
• Analysis of beta-catenin subcellular localization and Wnt target gene expression (e.g., CMYC, OCT4, NANOG, CCND1).
• Assessment of oncogenic phenotypes including cell migration, proliferation, spheroid formation, and in vivo tumor growth in breast cancer models.

Main Results:

• Acetylation of K34 in the DIX domain regulates beta-catenin localization and downstream Wnt target gene expression.
• K69 (DIX domain) and K285 (PDZ domain) acetylation modulate DVL-1 binding to Wnt target gene promoters, affecting gene expression.
• Conserved DVL-1 lysines influence critical oncogenic functions and in vivo tumor growth in breast cancer models.

Conclusions:

• Domain-specific lysine acetylation of DVL-1 plays a crucial role in modulating Wnt signaling and oncogenic processes.
• These findings highlight DVL-1 acetylation as a potential target for therapeutic intervention in cancers with dysregulated Wnt signaling.
• DVL-1 lysine modifications may possess prognostic utility for guiding translational cancer therapies.