Deubiquitinases in Cancer and HealthResearch Proposal

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¶ … Prostate cancer is the second leading cause of cancer death in men (U.S. Centers for Disease Control and Prevention, 2014) and prostate tumors express high levels of the ubiquitin-specific protease-14 (USP14) (Human Protein Atlas, n.d.). USP14 is the mammalian ortholog of the yeast deubiquitinase (DUB) Ubp6 and Ubp6/USP14 has been shown to reversibly associate with the19S RP proteosomal subunit (D'Arcy, Wang, & Linder, 2015). Association with the 19S RP subunit and assembly of the 26S proteosome complex induces Ubp6/USP14-mediated DUB activity nearly 1,000-fold. Ubp6/USP14 trims polyubiquitin moieties to ease capture by the proteosome, delays processing of captured protein sufficiently to allow ubiquitin removal and rerelease into the cytosol, and participates in ubiquitin recycling.

Ubp6/USP14 protein has an N-terminal ubiquitin-like domain (UBL) and catalytic domain (D'Arcy, Wang, & Linder, 2015). Cys114, His435, and Asp451 represent the active site and mediate enzymatic activity similar to that of papain cysteine proteases. The active site remains occluded by two loops in cytosolic Ubp6/USP14, but association with 19S RP is believed to induce a conformation change that exposes the ubiquitin-binding site. The preferred substrate of USP14 is polyubiquitin chains joined by Lys48. USP14 DUB activity can be inhibited by several small molecule inhibitors and treatment with IU1 inhibits polyubiquitin trimming and enhances proteosomal activity. USP14-null mice are grossly normal except for synaptic abnormalities, which suggest normal ubiquitin recycling in synapses depends on USP14 activity.

Recent research findings suggest autophagy may play an important role in the repair of DNA double-strand breaks (DSBs), based on evidence showing inhibition of autophagy sensitizes cells to ionizing radiation (Liu et al., 2015). Research findings have also revealed ubiquitylation plays a critical regulatory role in autophagy, as does the trimming of ubiquitin moieties by DUBs (Vogel et al., 2015). Interestingly, ubiquitylation also plays an important regulatory role in the repair of DSBs, as do DUBs (D'Arcy, Wang, & Linder, 2015). A number of small molecule DUB inhibitors have been identified and characterized, raising the possibility of their therapeutic potential.

There are a large number of USP proteases with diverse activities and some researchers believe this may be a reflection of the high E3 ligase diversity (D'Arcy, Wang, & Linder, 2015). USP proteases are involved in a number of important cellular processes, including repair of DSBs and autophagy. USP10, for example, deubiquitinates p53, thereby preventing nuclear export and degradation in opposition to ubiquitylation by Mdm2. The kinase Ataxia telangiectasia mutated (ATM) phosphorylates cytosolic USP10 in response to DNA damage, stabilizing USP10 and allowing nuclear entry. In the presence of wild-type p53, USP10 inhibits tumor growth, but in cells with a p53 loss-of-function mutation USP10 promotes proliferation. The mechanistic link between autophagy and repair of DSBs may depend in part on DUB activity, since Beclin-1, an adapter protein critical to the assembly of phagophores, increases the stability of USP10 and USP13. Relevantly, human breast, ovarian, and prostate tumor cells have lost one beclin-1 allele and belcin-1 heterozygous-null mice more readily develop lymphomas, carcinomas, and other cancers (Glick, Barth, & Macleod, 2010).

Whether USP14 plays a similar role in BER and autophagy in prostate cancer is the focus of this proposal. At a minimum, inhibition of USP14 activity would be predicted to increase proteosome activity and the degradation of proteins that would otherwise remain active. If USP14 also plays a role in DSB repair in a manner similar to USP10, then inhibiting USP14 activity in tumor cells with a p53 loss-of-function mutation would tend to induce growth arrest and possibly senescence. Since prostate tumors tend to express moderate to high levels of USP14 and p53 activity is abrogated by either genetic mutation or Mdm1 over-expression in approximately 55% of early stage tumors, inhibiting USP14 activity may restore proteosome activity and inhibit tumor growth, if the roles of USP14 in prostate tumors is similar to that of USP10. In addition, USP14 inhibition may render prostate tumors sensitive to ionizing radiation based on recent research findings (Vogel et al., 2015; Liu et al., 2015). For these reasons, we hypothesize that inhibition of USP14 will sensitize prostate cancer cells to ionizing radiation by inhibiting DSB repair.

The first specific aim of this proposal will examine the role of ?-H2AX deubiquitination in NHEJ repair pathway in autophagy-deficient cells. Autophagy-deficient cells can be created in vitro by treatment with either Vorinostat or… [END OF PREVIEW]

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