Phosphorylation-dependent STAMBP drives the progression of pancreatic ductal adenocarcinoma by deubiquitinating and stabilizing BAG3.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is usually diagnosed at a late stage and has a modest clinical response and poor prognosis. Therefore, identifying targets for the effective treatment of PDAC is particularly important. STAM-binding protein (STAMBP) is a JAMM metalloprotease of the deubiquitinase (DUB) family that typically regulates the stabilization and trafficking of substrates in a range of cell types by specifically removing ubiquitin chains. However, its roles in the initiation and progression of PDAC remain unclear. Here, we found that STAMBP is highly expressed in PDAC and is associated with a poor prognosis. STAMBP facilitates the proliferation and migration of PDAC cells and the growth of pancreatic cancer xenograft tumours in mice. We then identified the cochaperone BAG3, which plays a pivotal role in tumourigenesis, as a potential substrate of STAMBP using mass spectrometry (MS). Mechanistically, STAMBP interacts with BAG3 and promotes its stabilization by removing its K63-linked polyubiquitin chains. The Lys29 and Lys60 residues of BAG3 are essential for the K63-linked ubiquitination of BAG3. Moreover, a phosphorylation-dependent mechanism of STAMBP was identified as follows: STAMBP is phosphorylated by IKKα at Ser2 without affecting STAMBP protein abundance, and this phosphorylation enables it to deubiquitinate BAG3. In addition, we found that STAMBP deficiency effectively increases cisplatin/oxaliplatin sensitivity in PDAC. Overall, IKKα phosphorylates STAMBP at Ser 2, which activates STAMBP to deubiquitinase BAG3, thus resulting in an IKKα/STAMBP/BAG3 signaling axis that promotes PDAC progression. STAMBP might serve as a potential therapeutic target for PDAC therapy.