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Figure 7. Comparison study for ubiquitin-specific peptidase 22 expression with TP53 mutation status. Number of patients are in
parenthesis

disease. Further analysis of GSE54460 expression data supports increased USP22 expression with higher
grades of PCa [Figure 6]. Moreover, advanced PCa patients often have functionally inactive TP53.
Oncomine analysis of the Grasso cohort indicates that TP53 mutation is associated with increased
[75]
expression of USP22 [Figure 7] . Therefore, primary PCa patients who have higher expression of USP22
with functionally inactive TP53 might be candidates for alternative therapeutic approaches. Various clinical
trials are currently ongoing with upfront administration of chemotherapy such as cabazitaxel for patients
who have started to develop disease progression in the early stage. In future, analysis of such cohorts will
address whether such therapy can be beneficial for those who have showed early upregulation of USP22
expression.

To mimic that hyperactivation/overexpression state, the role of USP22 functions in PCa progression has
recently been redefined in a genetically modified mouse model. According to the model, prostate specific
upregulation of USP22 is associated with a hyperproliferative phenotype, an indication of aberrant cell
proliferation. Moreover, studies have also showed that overexpression of USP22 is important for cellular
survival following a genotoxic insult by DNA-damaging agents. In line with their finding, the authors have
identified the nucleotide excision repair pathway protein XPC as a substrate for USP22, which modulate
XPC polyubiquitination status following the DNA-damage response and thereby, efficiently recruited it
into the damage foci. Interestingly, the depletion of USP22 in PCa cells affects efficient DNA repair and
[19]
therefore, presents a therapeutic challenge .
Although USP22 was identified almost 15 years earlier as an important oncogenic driver for therapy
resistant prostate cancer, not much work has been carried out to understand its importance in the
development of mCRPC. As part of the SAGA complex, how inappropriate stoichiometric upregulation of
USP22 in PCa drives AR/Myc mediated gene-expression remains unresolved. Also, whether USP22 plays
an independent role in PCa progression is not well understood.

OTHER USPS IN PROSTATE CANCERS
Importantly, other ubiquitin specific proteases or USPs have long been recognized in the progression of
advanced PCa.

USP2a (also known as USP2) has been associated with PCa development. More than 50% of cases with PCa
have USP2a overexpression. Increase in USP2a selectively deubiquitinates and stabilizes MDM2, which