JAB1/CRL4B Complex Represses PPARG/ACSL5 Expression to Promote Breast Tumorigenesis

Fatty acid metabolism is critical for tumor progression, supplying bioenergetic and biosynthetic substrates to rapidly proliferating cancer cells. However, the precise mechanisms by which fatty acid metabolism influences breast cancer progression remain unclear. In this study, we aimed to explore the molecular mechanism by which JAB1 promotes breast cancer progression through regulating fatty acid metabolism. Our results shows that C-Jun activation domain-binding protein-1 (JAB1) is identified as an oncogene in breast cancer. JAB1 stabilizes CUL4B expression via deubiquitination, thereby promoting cell proliferation, invasion, and stemness. Mechanistically, JAB1 forms a transcriptional repressor complex with the Cullin 4B-Ring E3 ligase (CRL4B) complex, and co-occupy on the promoters of key fatty acid metabolism genes, PPARG and ACSL5, thus leading to their transcriptional repression. This disrupts fatty acid metabolism, increases mitochondrial oxygen consumption, and provide the energetic demands to breast cancer cells. Notably, JAB1 inhibition reverses chemotherapy resistance associated with CUL4B overexpression. These findings underscore the pivotal role of JAB1 in regulating breast cancer progression and indicate that JAB1 inhibitors could serve as promising therapeutics for patients with the elevated CUL4B expression.