An active homeostatic system controls numerous intracellular proteins through a complex regulatory system of protein synthesis, folding, and degradation. This process is called proteostasis and should be highly regulated for maintaining homeostasis in the cell and avoiding the diseases progression. Apoptosis is activated during extensive cellular damage and insufficient adaptive responses. Protein-folding can be impaired under stressful conditions such as heat, oxidative stress, hypoxia or damage to DNA, leading to the accumulation of misfolded proteins which induces apoptosis [1]. These processes highlight the essential role of proteostasis in preserving cellular integrity, protein function, and cell survival. These processes highlight the critical role of proteostasis in maintaining cellular integrity, appropriate protein function, and cell survival.

One of the most significant cellular recycling systems is the ubiquitin-proteasome system (UPS), which degrades over 80% of the intracellular proteins in the cells [2]. UPS controls essential cellular processes such as apoptosis, gene expression, and cell cycle progression through ubiquitination. Despite its small size and high evolutionary conservation, ubiquitin serves as a highly flexible and versatile regulatory molecule which covalently binds to target proteins and forms polyubiquitin chains. The essential components of the UPS protein degradation system are ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin ligases (E3), and the proteasome (a protein-digesting organelle). Conversely, deubiquitination has associated with multiple biological functions and development and progression of different cancers [3]. DUB inhibitors are identified novel therapeutic molecules and have potential for developing targeted anti-cancer therapy in many types of cancer.

Besides general description of the UPS, this review addresses the functions and regulatory processes of deubiquitinases and summarizes the diversity of their subfamilies. The review also describes that DUBs may either favor or inhibit cancer, depending on the cellular setting, which shows its diverse and complex features. It further emphasizes the potential of targeting deubiquitinases as a strategy for cancer therapy.