USP44 suppresses pancreatic cancer progression and overcomes gemcitabine resistance by deubiquitinating FBP1.

Pancreatic ductal adenocarcinoma (PDAC) is considered to be the deadliest cancer type in the world. Chemotherapy resistance, including gemcitabine, is the main reason for poor prognosis in PDAC patients. Increased aerobic glycolysis is involved in chemotherapy resistance in PDAC. Fructose-1,6-bisphosphatase (FBP1) is one of the key enzymes in the process of gluconeogenesis and negatively regulates aerobic glycolysis. FBP1 loss is common in PDAC patient specimens and is associated with gemcitabine resistance by activating the MAPK pathway. While the regulatory mechanism of FBP1 in pancreatic cancer remains un-elucidated. Here, we found that ubiquitin-specific protease 44 (USP44) was down-regulated in PDAC patients, and USP44 might be a prognostic marker for PDAC patients. USP44 inhibit tumor cells progression and regulated gemcitabine resistance in PDAC. Importantly, we revealed USP44 promoted FBP1 deubiquitination to increase FBP1 protein expression in pancreatic cancer, which might be one of the underlying mechanisms of USP44 impeding the progression of pancreatic cancer. Collectively, the recognition of USP44 in the stabilization of FBP1 indicates USP44 might be considered as a new prognostic marker for pancreatic cancer therapy.