Research Progress for Targeting Deubiquitinases in Gastric Cancers

SIMPLE SUMMARY: The deubiquitinase-mediated cleavage of ubiquitin chains from substrate proteins plays a crucial role in regulating protein degradation, activities, interactions, and localization. The dysregulation of multiple deubiquitinases has been implicated in various human diseases, especially cancer. More importantly, many small molecules targeting oncogenic deubiquitinases have been discovered, some of which have exhibited promising anti-cancer effects and entered clinical trials. Gastric cancer remains one of the most common and fatal malignancies. In this review, we aim to summarize the multifaceted roles of deubiquitinases in gastric tumorigenesis. We also present the upstream regulation of specific deubiquitinases and the research progress of several deubiquitinase-associated small molecules for gastric cancer therapy. Together, this review will improve our understanding of the biological role of deubiquitinases as well as the therapeutic potential of targeting deubiquitinases in gastric cancer. ABSTRACT: Gastric cancers (GCs) are malignant tumors with a high incidence that threaten global public health. Despite advances in GC diagnosis and treatment, the prognosis remains poor. Therefore, the mechanisms underlying GC progression need to be identified to develop prognostic biomarkers and therapeutic targets. Ubiquitination, a post-translational modification that regulates the stability, activity, localization, and interactions of target proteins, can be reversed by deubiquitinases (DUBs), which can remove ubiquitin monomers or polymers from modified proteins. The dysfunction of DUBs has been closely linked to tumorigenesis in various cancer types, and targeting certain DUBs may provide a potential option for cancer therapy. Multiple DUBs have been demonstrated to function as oncogenes or tumor suppressors in GC. In this review, we summarize the DUBs involved in GC and their associated upstream regulation and downstream mechanisms and present the benefits of targeting DUBs for GC treatment, which could provide new insights for GC diagnosis and therapy.