A review of deubiquitinases and thier roles in tumorigenesis and development

Abstract

Ubiquitin is a small protein that can be added onto target protein for inducing target degradation, thereby modulating the activity and stability of protein. Relatively, deubiquitinases (DUBs), a class catalase that can remove ubiquitin from substrate protein, provide a positive regulation of the protein amount at transcription level, post-translational modification, protein interaction, etc. The reversible and dynamic ubiquitination-deubiquitination process plays an essential role in maintaining protein homeostasis, which is critical to almost all the biological processes. Therefore, the metabolic dysregulation of deubiquitinases often lead to serious consequences, including the growth and metastasis of tumors. Accordingly, deubiquitinases can be served as key drug targets for the treatment of tumors. The small molecule inhibitors targeting deubiquitinases has become one of the hot spots of anti-tumor drug research areas. This review concentrated on the function and mechanism of deubiquitinase system in the proliferation, apoptosis, metastasis and autophagy of tumor cells. The research status of small molecule inhibitors of specific deubiquitinases in tumor treatment is introduced, aiming to provide reference for the development of clinical targeted drugs.

Keywords: cancer; deubiquitinase; deubiquitinase inhibitor; deubiquitination; tumor treatment.

FIGURE 1

Process of Ubiquitination and deubiquitination. Ubiquitin-activating enzyme E1 initiates the ubiquitination process by activating ubiquitin in dependence on ATP. Subsequently, the activated ubiquitin is transferred onto the ubiquitin-binding enzyme E2. Subsequently, the target protein is recognized with the cooperation of ubiquitin ligase E3. As a result, ubiquitin can bind to the target protein’s Lys residue, thereby triggering a series of enzymatic reactions and eventually inducing hydrolysis of target protein by protease. DUBs can hydrolyze the peptide bond of ubiquitin, separate ubiquitin from the substrate protein, and induce deubiquitination.

FIGURE 2

Effect of DUBs on tumor cell proliferation. ABRO1 recruits USP7 and induces deubiquitination of Mdm2 and P53; USP21 induces FOXM1 and MEK2 deubiquitination; USP14 and USP22 can activate PI3K via the Wnt/β-catenin pathway. USP43 inhibits the degradation of ZEB1 protein by deubiquitination; OTUD6A can stabilize DRP1 by deubiquitination; All the processes promote the proliferation of tumor cells.