DUBs are involved in cell cycle
DUBs are involved in ptc124 regulation and DNA damage pathways and since, in cancer and different stress conditions all the proteins which regulate cell cycle and DNA damage/repair are either up/down regulated (Singh et al., 2013, Singh et al., 2011, Kumar and de Massy, 2010, Gupta et al., 2010), it would be interesting to investigate the potential role of DUBs in cell cycle and DNA damage/repair. In most of the cancers, tumor suppresser genes are degraded by ubiquitin which can be rescued by application of controlled mechanism of enhancing deubiquitinases in the tumor cells, to prevent degradation of tumor suppresser proteins. Development of small molecules which inhibits DUBs would be a great idea to target cancer cells and it will be facilitated by the development of suitable high throughput screening. Two molecules were identified that inhibit the SARS coronavirus DUBs papain like protease (PLpro) (Ratia et al., 2008, Ghosh et al., 2009). Some small molecules inhibit USP7 and USP8 (Daviet and Colland, 2008). Compound like G5 and F6 were reported as total DUBs inhibitor (Aleo et al., 2006) along with USP2, USP7 and SENP2 deSUMOylase (Aleo et al., 2006, Fontanini et al., 2009, Nicholson et al., 2008). b-AP15 was identified as an USP14 and UCHL5 inhibitor at a concentration of about 5μM (D'Arcy et al., 2011). AM146, RA-14, RAMB1, RA-9 and WP1130 are other molecules which inhibit many DUBs including USPs and UCH and induce accumulation of polyubiquitinated proteins (Anchoori et al., 2011, Issaenko and Amerik, 2012, Kapuria et al., 2010). WP1130 in combination with bortezomid had showed antitumor activity in mantle cell lymphoma (Pham et al., 2010). Several other small molecules have been reported as DUBs inhibitors like Eeyarestatin (Fiebiger et al., 2004), Velcade (Bold, 2004) and Kyprolis (Steele, 2013).
DUBs in immunotherapy P53 is a well known tumor repressor protein involves in cell cycle control and frequently mutated in tumor cells (Harris and Levine, 2005). Many of the USPs involve in P53 regulation. USP7 and USP15 involve in the control of P53-MDM2 pathway by regulating the stability of both P53 and MDM2 (Kon et al., 2010, Zou et al., 2014). USP2, USP4, USP5, USP10 and USP29 also involve in the regulation of P53 activity (D'Arcy et al., 2015). TNF-κB is another vital player in an immune response system which frequently deregulated and constitutively activated in cancer cells. Many DUBs like A20 and CYLD act as tumor repressor through their ability to downregulate TNF-κB signaling by acting on several components of the pathway (Harhaj and Dixit, 2012). USP21 and Cezanne inhibit TNF-κB activation by regulating ubiquitin level of RIPK1 (D'Arcy et al., 2015). Dr. Greenberg group from University of Pennsylvania showed that BRCC36 containing deubiquitinating complex BRISC which is also a sister protein complex of nuclear RAP80-BRCA1 complex, deubiquitinates type I interferon receptor (IFNAR1), resulting in its delayed lysosomal dependent degradation. They showed that BRISC deficient cells shows reduced inflammatory gene expression and BRISC deficient mice have an attenuated interferon response with a survival advantage from a LPS dependent septic shock (Zheng et al., 2013). All the above mentioned DUSs could be the potential candidate for immunotherapy.
Conflict of interest