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

BRD7 serves as a critical tumor suppressor, yet it is frequently inactivated via ubiquitination-mediated proteasomal degradation, facilitating tumor progression and metastasis. Although stabilizing or activating BRD7 represents a promising therapeutic strategy, pharmacological agents to achieve this remain limited. Here, we aimed to develop a peptide-based approach to enhance BRD7 protein stability. We first mapped the TRIM28-BRD7 interaction to the 299-349 aa region within the Coiled-coil domain of TRIM28. Based on this interface, we designed two α-helical peptides, TAB12 and TAB14, that mimic the key structural features. Mechanistically, TAB12 exhibits strong binding affinity toward BRD7 protein and competitively disrupts the TRIM28-BRD7 interaction, thereby blocking TRIM28-mediated BRD7 ubiquitination and stabilizing endogenous BRD7. In vitro functional assays demonstrated that TAB12 markedly inhibits tumor cell proliferation, migration, and invasion, induces cell apoptosis, and presents low cytotoxicity toward normal cells. Subsequent rescue experiments confirmed that BRD7 knockdown substantially abrogates the anti-tumor effects of TAB12, verifying that TAB12's function depends on stabilizing BRD7. Furthermore, in vivo animal models validated that TAB12 significantly suppresses tumor growth with a favorable safety profile. Therefore, this study identifies a novel peptide agent that exerts broad anti-tumor effects by stabilizing BRD7, offering a feasible strategy for restoring tumor suppressor function.