Page 172 - Read Online

Nag et al. J Cancer Metastasis Treat 2020;6:16 I http://dx.doi.org/10.20517/2394-4722.2020.23 Page 9 of 13

is important for the proteasomal degradation of p53 in PCa cells. p53 is the negative regulator of Myc
in many cases. USP2a mediated enhanced stability of MDM2 abrogates p53 accumulation and its tumor
suppressive functions. Therefore, the inhibition of p53 mediated transactivation of transcriptional activity
indirectly stabilizes Myc accumulation in cells and thereby, enhances the development of aggressive PCa
transformation. The deubiquitination activity of USP2a was also found to stabilize the anti-apoptotic gene
fatty acid synthase and thereby induce cells to develop neoplastic transformation. The depletion of USP2a
has also been shown to abrogate such cellular transformation [76,77] .

USP7 has been associated with PCa and plays a negative role for PTEN nuclear localization. PTEN
is generally regarded as a protein phosphatase that dephosphorylates the phosphatidylinositol
(3,4,5)-triphosphate to inhibit AKT signaling. However, PTEN’s role in the nuclear DNA repair system
associated with tumor suppressive functions has been well recognized. Following mono-ubiquitination,
PTEN moves into the nucleus and participates in the repair processes. In PCa, over-expression of USP7
expels this ubiquitinated-PTEN to the cytosol and activates the cells towards transformation. Interestingly,
in the presence of androgen, USP7 was identified as a co-regulator of AR. Studies also suggest that USP7
mediated AR-deubiquitination enhance the AR-transcriptional ability that promotes cell proliferation
and PCa aggressiveness. Moreover, single nucleotide polymorphisms that affect USP7 function has been
associated with the development of intermediate risk PCas [78,79] .

USP19 silencing directly affects the growth of several prostate cancer cell lines, suggesting a putative role in
[80]
carcinogenesis . USP19 deubiquitinates and stabilizes KPC1, an E3 ligase for p27. Interestingly, the effects
of decreased nuclear levels of p27, resulting in a poor prognosis, have already been described in prostate
[81]
cancer . USP19 regulates the levels of p27, although p27 is not a USP19 substrate. Reports indicate that
the disruption of USP19 inhibits a series of PCa cell proliferation by arresting cells in the G1 to S phase
[80]
transition through stabilization of the cyclin-dependent kinase inhibitor p27 . Increased stability of AR
by USP12, USP14 and USP26 has been linked to the development of aggressive PCa [82-84] . Recent reports
indicate that the overexpression of USP33 in PCa confers docetaxel resistance by inhibiting JNK activation
[85]
and apoptosis .

In the context of PCa, most USPs are overexpressed; however, USP9x was found to be down regulated in
advanced PCa and was associated with higher Gleason scores. This downregulation increases the local
[86]
invasiveness of PCa cells, possibly through the ERK activation pathway .
Among all the DUBs, available data suggest that USP22 functions often overlapped with other reported
USPs in the context of progression and development of therapy resistant PCas. Therefore, USP22 targeted
therapy or broad-spectrum inhibitors that can abrogate the functions of a group of USPs may be a better
therapeutic agent in PCa.

TARGETING USP22 IN ADVANCED PROSTATE CANCER TREATMENT
Recent studies have suggested that USP22 is emerging as a potential oncogenic driver in relation to PCa.
As a member of the cysteine protease family, its catalytic domains are somewhat conserved amongst family
members. Therefore, the development of inhibitors specifically against one such member is challenging.
Efforts have been made to develop small molecule inhibitors against the allosteric sites of USP22.
However, till now, no such specific inhibitor has been validated to target USP22. Recently, Pirarubicin
(4’-O-tetrahydropyranyl doxorubicin, THP), an anthracycline (analogue of another chemotherapeutic agent
[87]
known as doxorubicin), has been shown to inhibit USP22 expression in a condition-specific manner .
Reports indicated that protein kinase A (PKA), protein kinase B or mitogen activated kinase-mediated
phosphorylation of CREB-1 bind and activate the USP22 promoter for its synthesis. The addition of THP
abrogates PKA activity and decreases CREB-1 phosphorylation,, thereby inhibiting USP22 expression and