br Deubiquitination deubiquitinases and cancer Protein deubi
Deubiquitination, deubiquitinases and cancer Protein deubiquitination is reverse process of ubiquitination and performed by deubiquitinases or deubiquitinating enzymes (DUBs), which help in removal of ubiquitin from target proteins and involve in ubiquitin maturation, recycling and editing (Pfoh et al., 2015, Kim et al., 2003, Amerik and Hochstrasser, 2004, Nijman et al., 2005a, Reyes-Turcu and Wilkinson, 2009, Clague et al., 2013, Tyagi et al., 2015a). The function of deubiquitinases however, are rescuing the protein which is marked for degradation, and releasing ubiquitin from target proteins substrate. Dubs are playing an important role in cell growth, apoptosis and cancer (Pfoh et al., 2015, Hu et al., 2005, Avvakumov et al., 2006, Renatus et al., 2006) and are associated with 26S proteasome to rescue ubiquitin chain before the degradation of the substrate protein. These free polyubiquitin chains are processed by other DUBs to restore the ubiquitin in the cell (Pfoh et al., 2015). Approximately hundred human DUBs are discovered till date and these are divided into four classes; (1) ubiquitin specific proteases (USP), (2) ubiquitin C-terminal hydrolases (UCH), (3) ovarian tumor proteases (OTU), (4) Josephins and the Jab1/MPN/MOV34 metalloenzymes (JAMM). USPs are the major DUBs and are associated with most of the cancers and play an important role in regulation of various pathways, for example in Fanconi Anemia (FA). FA is a genomic instability syndrome characterized by bone marrow failure, developmental abnormalities and increased probability of cancers (Kee and D'Andrea, 2010). There are many reports, based on clinical investigation indicated that FA is a chromosomal instability disorder, and LiCl from FA patients accumulate DNA damage at an increased rate. Mono-ubiquitination of FANCD2 and FANCI is a vital event in FA pathway, downstream of this pathway, it interacts with FAND1, FANCN, FANCJ and BRCA1 (Knipscheer et al., 2009). USP1/UAF1 is known to deubiquitinases FANCD2 and FANCI. Disruption of USP1/UAF1 complex promote level of FANCD2/FANCI ubiquitination and DNA repair defects, suggesting a failure in the completion of FA pathway (Nijman et al., 2005b, Smogorzewska et al., 2007). ELG1 (Enhanced Levels of Genomic Instability) are recently found associated with USP1/USF1 and may play a role in the successful completion of the FA pathway (Lee et al., 2010, Yang et al., 2011, Shkedy et al., 2015). Ubiquitin C-terminal hydrolase-L1 (UCTL1), is one of the most explored DUBs which is involved in neurodegenerative disorders such as Parkinson disease. It has been shown that expression of neurons of neuroendocrine system and gonads is unregulated in non-small cell lung cancer (Hibi et al., 1998, Hibi et al., 1999), oesophageal cancer (Takase et al., 2003) invasive colorectal cancer (Yamazaki et al., 2002) and pancreatic cancer (Tezel et al., 2000). Overexpression of the UCHL-1 has also been related with tumor progression, size, invasiveness and apoptosis in breast cancer (Wang et al., 2008). Mechanism of action and potential role of different DUBs in the different cancers is well established (D'Arcy et al., 2015, Pfoh et al., 2015, Sacco et al., 2010) and shown in Table 1, Table 2.
Therapeutic potential of DUBs for the treatment of cancer Accumulation of genetic mutations and aberrant signaling of various growth and survival related pathways in cancer cells (Tyagi et al., 2015b, Tyagi et al., 2015c, Srivastava et al., 2015, Arora et al., 2015, Tyagi et al., 2014) leads to the clinical diversity and therapeutic resistance. However, advance understanding of the complex biology of cancer cells (Tyagi and Ghosh, 2011, Tyagi et al., 2011, Bhardwaj et al., 2014, Deshmukh et al., 2015) and the involvement of deubiquitinating enzymes in cancer (Schubert et al., 2000, Ciechanover, 2006, Pfoh et al., 2015) reveals the therapeutic potential of DUBs for the treatment of cancer. As mentioned in Table 2, DUBs are playing an important role in different type of cancers. More extensive studies are needed in this area of research to explore the detailed mechanism and target of DUBs. Study and designing the targeted small molecule DUB inhibitors, will most probably a new therapeutics for different types of cancers. DUBs have been identified in most of the cancer (Table 2) and targeting them can be an effective way to treat, diagnose and prevent the disease.