Ubiquitin-specific proteases in pancreatic cancer: Molecular regulators of tumor progression and therapy resistance

Pancreatic cancer is caused by a complicated set of molecular changes that include genetic mutations and aberrant signaling pathways, which result in tumor growth, metastatic spread, and resistance to therapeutics. Of the various molecular changes, standard modifying processes, such as ubiquitination and deubiquitination, influence protein levels, cellular localization, and protein function. In this context, ubiquitin-specific proteases (USPs), a primary class of deubiquitinases (DUBs), play a crucial role in regulating the ubiquitin-proteasome system, which controls protein degradation and activity in cells. These USPs can cause the removal of ubiquitin from target proteins, thereby reversing the ubiquitination process. They are key for maintaining cellular homeostasis by regulating the turnover of proteins, including those responsible for signal transduction, cellular processes (such as the cell cycle), and the response to stress events. At the same time, USPs (including USP21, USP13, USP51, and USP22) also affect multiple signaling pathways, including the Wnt, NF-κB, and TGF-β pathways, all of which are involved in the biology of pancreatic cancer. USPs will promote or inhibit cancer-associated pathways that drive proliferation, metastasis, immune evasion, and therapy resistance by stabilizing or destabilizing specific signaling molecules. This review will examine the mechanistic roles of USPs in pancreatic cancer, as well as the tumor behavior and therapeutic resistance that may result from the dysregulation of these proteins. Ultimately, by presenting an opportunity to develop targeted therapies against specific USPs, we hope to emphasize new therapeutic strategies that could positively impact the lives of patients suffering from this aggressive disease.