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Page 2 of 13 Nag et al. J Cancer Metastasis Treat 2020;6:16 I http://dx.doi.org/10.20517/2394-4722.2020.23
[2-5]
6 months to 2 years in the form of highly aggressive castration resistant prostate cancer (CRPC) . While
the treatment of CRPC with second generation ADT such as Abiraterone or Enzalutamide is promising,
eventually, the cancer progresses to metastatic disease [called metastatic CRPC (mCRPC)], especially in
[6]
the bone . Chemotherapy with docetaxel is the first choice for treatment with mCRPC. Unfortunately,
mCRPC patients have died due to complications related to metastatic transformation of PCa [7-11] .
Interestingly, these mCRPC often lose the androgen-receptor dependency and are associated with the loss
of tumor suppressor proteins such as tumor protein p53 (TP53) and retinoblastoma 1 (RB1) [12,13] . Genome-
wide sequencing analysis has found some of the unique variations in the chromosomal sequence but no
such driver mutation/s in PCa has been ascertained to correlate with cancer progression [14-16] . Moreover,
not all primary PCa cases progress to CRPC. Therefore, to understand the indolent vs. aggressive nature
of PCa, gene-expression analysis is highly important. To correlate CRPC progression and to stratify the
therapeutic regimen, high throughput sequencing analysis of various stages of PCa to correlate genetic
expression profiles with the therapy-resistant state has been attempted. The expression of a 11-gene
[17]
signature in primary prostate tumors was shown to correlate with therapeutic failure in PCa patients .
Further characterization has shown that this 11-gene signature is a powerful predictor of distant metastasis
and poor survival. Amongst these eleven genes, a specific deubiquitinases, named USP22, has been over-
expressed following PCa progression. Further evidence indicates the importance of USP22 in a multi-faced
pathway, which often correlates with a poor prognosis of PCa independently [18-20] .

CLASSIFICATION OF DEUBIQUITINATING ENZYMES
The protein ubiquitin (Ub) plays an important role in tissue homeostasis. Ub modification is a reversible
phenomenon that is coordinated by the deubiquitination pathway [21-24] . Deubiquitinating enzymes (DUBs)
belong to either cysteine proteases [such as ubiquitin-specific proteases (USPs), ubiquitin C-terminal
hydrolases (UCHs), etc.] or metalloproteases [Jab1/Mov34/Mpr1 (JAMM)], which are important for
maintaining normal physiological homeostasis [21,25] . Approximately 100 DUBs are encoded in the human
genome. DUBs are involved in various physiological processes including the processing of Ub precursors,
reversal of ubiquitination and removal of poly-ubiquitin chains [20,26] . Therefore, DUBs regulate a series of
cellular processes and functions including proteolysis, apoptosis, cell cycle progression, gene expression,
DNA repair, maintenance of telomeric length, spermatogenesis, and so on [27-30] . One such conserved
ubiquitin-specific protease is USP22 and it has been well characterized, relating to various physiological
and pathological processes [19,31] .

UBIQUITIN-SPECIFIC PEPTIDASE 22
The ubiquitin-specific peptidase 22 (USP22) belongs to the USPs family of DUBs and is highly conserved
from yeast to vertebrates. In yeast, the USP22 homologue known as Ubp8, is complexed with Sgf73, Sgf11
and Sus1 to form the deubiquitylase module (DUBm) of the SAGA (Spt-Ada-Gcn5 Acetyl transferase)
complex. The SAGA complex has a multi-disciplinary role in gene-expression and RNA-transport. Like
yeast Ubp8, USP22 also forms a DUBm complex with the human orthologue ATXN7L3, ENY2 and ATXN7
and functions as a DUB unit of the human SAGA complex [32,33] .

ROLE OF USP22 IN CELLULAR PROCESSES
As a part of the SAGA complex, transcriptional activation by deubiquitination of lysine-123 of histone-
H2B is enhanced [34,35] . Later it was identified that histone-H2A ubiquitination can be processed by USP22.
Ubiquitination of H2A by the polycomb group of proteins is related to transcriptional repression. However,
whether deubiquitination of H2Aub (monoubiquitinated histone) by USP22 reverses the phenotype is not
[36]
yet clearly established .
Other than histones, USP22 also regulates the ubiquitination status of a large number of non-histone
proteins. One of the most important functions of USP22 is to regulate telomeric length. Telomeric repeat