E3 ubiquitin ligase DTX3L promotes breast cancer progression by enhancing PKCα ubiquitination and inhibiting the p38 MAPK signaling pathway.

E3 ubiquitin ligases are increasingly recognized for their critical role in tumor progression. While DTX3L, a member of the Deltex ligase family, has been linked to several cancers, its exact role in breast cancer (BC) was not well understood. Here, we report that high DTX3L expression in BC is associated with poor patient outcomes. Experimentally, DTX3L promoted BC cell proliferation, migration, and invasion, as well as tumor growth in vivo. Transcriptomic profiling after DTX3L knockdown showed significant enrichment of altered genes in the mitogen-activated protein kinase (MAPK) pathway. Accordingly, we found that DTX3L regulates p38 MAPK phosphorylation. Further investigation revealed that DTX3L binds protein kinase C alpha(PKCα) through its RING domain, targeting PKCα for K48-linked ubiquitination and proteasomal degradation. This process attenuates p38 MAPK phosphorylation, which in turn drives BC progression. Together, our work defines a key signaling axis-DTX3L-PKCα-p38 MAPK-in BC progression and provide important insights for the diagnosis and treatment of this disease.