BAP1 Represses Sequential Activation of IRAKs and NF-κB Signaling in Pancreatic Cancer

The deubiquitinating enzyme BRCA1 Associated Protein-1 (BAP1) has been reported to be shallowly deleted in a subset of pancreatic ductal adenocarcinomas (PDAC) and is believed to play a significant role in the development of chronic pancreatitis-driven PDAC. However, evidence suggests that BAP1 may also be involved in the progression and metastasis of PDAC, though the underlying mechanism remains unclear. Here, we demonstrate that BAP1 deletion leads to the overactivation of the nuclear factor-κB (NF-κB) signaling in PDAC, thereby promoting the proliferation, migration, and invasion of PDAC models both <i>in vivo</i> and <i>in vitro</i>. Mechanistically, BAP1 inhibits the sequential activation of interleukin-1 receptor-associated kinases (IRAKs) in an enzyme-independent manner. BAP1 binds to IRAK1 and inhibits the interaction between IRAK4 and IRAK1, as well as the IRAK4-mediated initiation of IRAK1 phosphorylation and autophosphorylation. This, in turn, prevents the dissociation of IRAK1 from the Myddosome complex and sequential activation of NF-κB. Based on this, we further identified that dual-target inhibitors of IRAK1/4 exhibited significant inhibitory effects on BAP1-deficient tumors in both <i>in vivo</i> and <i>in vitro</i> PDAC models. Our findings elucidate the mechanism by which BAP1 inhibits the NF-κB signaling and present a promising strategy for the targeted treatment of BAP1-deficient pancreatic cancer.