K11- and K29-ubiquitination-mediated nuclear translocation of glycolytic enzyme aldolase A promotes pancreatic cancer progression by NF-κB activation.

The function of cytosolic aldolase A (ALDOA) in glycolysis is well recognized. However, the cytosol-to-nucleus redistribution of ALDOA and its nuclear function is poorly understood. Here, we uncover inflammatory factor-stimulated nuclear function of ALDOA in augmenting pancreatic carcinogenesis by activating NF-κB signaling in a ubiquitination-dependent manner. TNF-α-triggered K11- and K29-linked ubiquitination of ALDOA at Lys200 promotes its interaction with RelA/p65 and facilitates importin-β-dependent nuclear translocation, establishing a positive feedback regulation in the tumor microenvironment by elevating the TNF-α expression in pancreatic ductal adenocarcinoma (PDAC). USP4 is identified as a negative regulator that deubiquitinates ALDOA. Instead of broadly targeting ALDOA, which causes glycolysis impairment, the specific elimination of ALDOA ubiquitination enhances chemosensitivity and the synergistic effect of chemotherapy combined with p65-specific anti-inflammatory therapy by selectively suppressing inflammation-induced proliferation in cancer cells. Collectively, we unveil the multifaceted mechanisms by which ALDOA promotes PDAC carcinogenesis, from metabolic to gene regulatory perspectives, providing potential therapies combatting cancer.