A USP28-BRD4 axis contributes to the acceleration of breast cancer growth by hyperglycemia.

Diabetes exacerbates breast cancer progression through incompletely understood mechanisms. BRD4, a bromodomain transcriptional coactivator recognizing histone lysine acetylation, is overexpressed in cancer and upregulates tumor-promoting genes. But its role in diabetes-promoted breast cancer growth remains unknown. Here, we report that hyperglycemia stabilizes BRD4 protein to accelerate breast cancer growth. Proximity labeling proteomics identifies the deubiquitinase USP28 as a direct interactor and stabilizer of BRD4. The USP28-BRD4 interaction and USP28-catalyzed BRD4 deubiquitination require USP28 acetylation at lysine 702 (K702). This acetylation, catalyzed by acetyltransferase KAT8 and antagonized by NAD+-dependent deacetylase SIRT1, creates a binding site recognized by the BRD4 bromodomain 1. Under diabetes, hyperglycemia reduces intracellular NAD+, impairing SIRT1 activity, enhancing USP28-K702 acetylation, strengthening USP28-BRD4 interaction, and increasing BRD4 stability. Functional studies demonstrate that the USP28-BRD4 axis is required for hyperglycemia-driven breast cancer growth. Collectively, our findings unveil the USP28-BRD4 axis as a mechanistic link between hyperglycemia and cancer progression.