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Nag et al. J Cancer Metastasis Treat 2020;6:16 I http://dx.doi.org/10.20517/2394-4722.2020.23 Page 5 of 13

Kras G12D/+ was associated with shorter survival compared to Kras G12D/+ mice. Further studies indicate
that mice that received myeloid progenitor cells carrying USP22 deletion and mutated Kras G12D/+ had an
AML phenotype. As a mechanism, USP22 was shown to positively regulate protein expression of the
transcription factor PU.1, which is important for myeloid and B-lymphoid cell development. Depletion of
USP22 directly affected myeloid specific gene expression in Kras G12D/+ mutated mice, which further led to
[68]
the development of AML . Contradictory functions of USP22 in the development of colorectal cancer
have been reported. One such study showed that intestine specific USP22 deletion impaired the tumor
phenotype associated with Apc mutation and positively correlated with the intestinal tumor burden and
decreased survival. Mechanistically, the loss of USP22 resulted in increased mTOR activity and has been
[69]
linked to the tumorigenic properties of colorectal carcinoma .
Over-expression of USP22 is observed in aggressive PCa and has been associated with its oncogenic
function. In the following section, we will concentrate mainly on the role of USP22 in the development of
CRPC and treatment-resistant PCa.

USP22 AND PROSTATE CANCER
During PCa progression, increase in copy numbers as well as enhanced expression of androgen receptor
(AR) (along with its splice variant formation) often led to aggressive therapy resistant phenotypes [70,71] .
Therefore, targeting AR is the most favorable choice to limit PCa progression. Over the years, improvement
in AR targeted therapy has increased overall survival to some extent, however, recent clinical studies
indicate that a individuals are becoming resistant to second generation anti-androgen therapy. Therefore,
understanding therapy resistance pathways may provide better or alternative solutions to target PCa. Since
the 11-gene signature was shown to predict PCa recurrence and therapy resistance, the contribution of
individual genes and 5-year PCa survival was analyzed in mCRPC cases. High expression of Ki-67, BUB1,
[18]
KNTC1 and USP22 showed significant association with poor 5-year survival . Further, it was shown
that the concerted expression of USP22, AR and Myc in PCa cells predicted the worst prognosis of the
disease. USP22 plays an important role in AR protein stability and recruitment to AR-binding regions to
drive AR driven cancer cell proliferation and tumor growth in CRPC cells. Later, it was shown that USP22
is equally important for protein stability of AR-variants. The upregulation of USP22 also promotes AR/
Myc driven gene expression independent of androgens in the CRPC cell line, implicating that USP22 has a
tremendous impact on genes that are regulated by AR and Myc in CRPC cells. This might be important to
[18]
the phenomenon of anti-androgen therapy resistance . Interestingly, analysis of patient data with mCRPC
[72]
validates that point (https://www.cbioportal.org/) . Analysis of the coordinated expression of USP22
and AR between abiraterone/enzalutamide (2nd generation anti-androgen therapy) in naïve vs. exposed
groups revealed that USP22/AR expression is upregulated in patients who have progressed to mCRPC
under treatment conditions. However, in the treatment naïve group, such correlation was not ascertained
[Figure 1]. Patients who are resistant to abiraterone/enzalutamide therapy often develop neuroendocrine-
like PCa. Further analysis of patient data (GSE126078) indicates that in pathologically validated
neuroendocrine PCa, USP22 expression is significantly higher compared to metastatic sites, which did
not develop the neuroendocrine phenotype [Figure 2]. In general, bone is the preferred metastatic site
for PCa. However, neuroendocrine PCas often develop visceral metastasis. USP22 expression in visceral
[72]
metastatic sites (https://www.cbioportal.org/) was significantly higher compared to bone [Figure 3].
Therefore, further validation of the earlier observations and selective upregulation of USP22 are associated
with therapy resistance and progression of the disease. This group of patients need an alternative form of
treatment and the early detection and stratification of these patients will be beneficial.

Increased expression of USP22 was also observed with progression of primary PCa. Analysis of the Oncomine
database showed that USP22 expression increases with increased Gleason score [Figures 4 and 5] [73,74] ,
indicating that during progression of PCa, USP22 expression can be a predictive factor for advanced