Deubiquitinases (DUBs, ubiquitin isopeptidases) are components of the ubiquitin proteasome system (UPS) that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. The majority of DUBs are cysteine proteases and are likely to be more "druggable" than E3 ligases. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles.
An Overview of Deubiquitinases
Deubiquitinases (DUBs, ubiquitin isopeptidases) are important parts of the ubiquitin proteasome system (UPS), which mainly removes ubiquitin molecules on the target protein and reverses the action of ubiquitin E3 ligase to control ubiquitin level in cells. DUBs play a very important role in the metabolic regulation of cells. Their functions involve many physiological and biochemical processes of cells, such as cell cycle regulation, DNA damage repair, and tumor development. Besides, DUBs can regulate cancer stem cells differentiation and pluripotency.
Major Types of Deubiquitinases
To date, there are six major classes of DUBs: UBP/USP family (ubiquitin-specific processing proteases), UCH family (ubiquitin carboxy terminal hydrolases), JAMM family (Jad1/Pad/MPN domain containing metallo enzymes), OTU-domain ubiquitin-aldehyde-binding protein, MJD family (Machado-Joseph disease related enzymes) and MCPIP family (monocyte chemotactic protein-induced protein).
Deubiquitinases and Diseases
DUBs and their deregulation have an impact on human diseases, such as cancer and neurodegeneration. DUBs affect the occurrence and development of tumors by regulating the degradation of various proteins in the body. An important way for DUBs to function is to promote or inhibit the development of cancer by regulating various signal pathways in the body to promote changes in the content of downstream related proteins. DUBs are involved in the regulation of Wnt/β-catenin signaling, transforming growth factor-β (TGF-β), protein kinase B (Akt), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and other cancer-related pathways. The identification of ubiquitin in protein aggregates associated with neurodegenerative pathologies, such as neurofibrillary tangles in Alzheimer’s disease.
The Inhibition of Deubiquitinases
A number of DUBs inhibitors have been designed based on the relevant pathways. P5091 is a small molecule inhibitor, and the overactivation of the former is associated with colorectal cancer and chronic lymphatic leukemia. RA-9 plays an important role in inhibiting the function of proteasome-associated DUBs. USP7 is currently an important targeting molecule for cancer therapy. The specific inhibitor of USP7, HBX 19818, can selectively reduce the activity of USP7 and thus play a role in the treatment of cancer. PR-619 is a non-specific inhibitor of DUBs that acts on a variety of DUBs. At present, the inhibitors of DUBs are mainly small molecule inhibitors, and no inhibitors have entered the clinical stage.
Lei, H., Shan, H. Z., Wu, Y. (2017) Targeting deubiquitinating enzymes in cancer stem cells. Cancer Cell Int, 17: 101.