TRIM28-Derived Peptide Exerts Anti-Tumor Roles by Stabilizing Tumor Suppressive BRD7 Protein in Multiple Cancers

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• BRD7 is a crucial tumor suppressor frequently inactivated by ubiquitination and proteasomal degradation.
• Limited pharmacological agents exist to stabilize or activate BRD7, hindering therapeutic strategies against cancer progression and metastasis.

Purpose of the Study:

• To develop a peptide-based therapeutic approach to enhance BRD7 protein stability.
• To investigate the mechanism of action and anti-tumor efficacy of the developed peptide.

Main Methods:

• Mapping the TRIM28-BRD7 interaction interface.
• Designing and synthesizing α-helical peptides (TAB12, TAB14) mimicking the interaction interface.
• Assessing peptide binding affinity, disruption of TRIM28-BRD7 interaction, and inhibition of BRD7 ubiquitination.
• Evaluating anti-tumor effects (proliferation, migration, invasion, apoptosis) in vitro and in vivo.
• Performing rescue experiments and safety profiling.

Main Results:

• The peptide TAB12 effectively binds BRD7 and disrupts the TRIM28-BRD7 interaction, inhibiting BRD7 ubiquitination and stabilizing endogenous BRD7.
• TAB12 demonstrated significant inhibition of tumor cell proliferation, migration, and invasion, alongside induction of apoptosis in vitro, with low cytotoxicity to normal cells.
• In vivo studies confirmed TAB12's tumor growth suppression in animal models with a favorable safety profile.
• Rescue experiments confirmed that TAB12's anti-tumor effects are dependent on BRD7 stabilization.

Conclusions:

• A novel peptide agent, TAB12, has been developed that stabilizes the tumor suppressor BRD7.
• TAB12 exerts broad anti-tumor effects by restoring BRD7 function, presenting a feasible therapeutic strategy for various cancers.
• This peptide-based approach offers a promising avenue for cancer therapy by targeting tumor suppressor stabilization.