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Page 10 of 13 Nag et al. J Cancer Metastasis Treat 2020;6:16 I http://dx.doi.org/10.20517/2394-4722.2020.23

Figure 8. Summary of ubiquitin-specific peptidase 22 (USP22) role in prostate cancer

USP22 mediated tumorigenic activity. Betulinic acid (BA), a small molecule isolated from white birch
trees, has been shown to inhibit an array of DUBs. BA was also showed to reduce AR protein stability and
selectively kills PCa cells. Another multi-DUB inhibitor WP1130 has been shown to selectively kill PCa
cells. Treatment with WP1130 also reduces AR expression in CRPC cells. Therefore, BA and WP1130 have
the potential to enhance the therapeutic efficacy of CRPC cells and the published literature suggests that the
combination of these inhibitors with enzalutamide increases the therapeutic window for the treatment of
[88]
advanced PCa patients . With such growing knowledge, scientists have tried to develop exosite inhibitors
against the various DUBs. One such inhibitor, P5091, is highly selective against USP7 and has been shown
to induce apoptotic cell death in therapy resistant multiple myeloma cells . However, its selectivity and
[89]
specificity as an agent in PCa remains unknown.

CONCLUSION
In summary, the oncogenic role of upregulated USP22 in the progression and development of treatment
[19]
resistance of PCas has been observed [Figure 8] . Accumulated evidence indicates that USP22 possibly
functions independent of the SAGA complex in the progression of PCas. Increased acetylation and
enhanced activity of GCN5 has been reported to be associated with advanced PCa. However, there is
a lack of studies to ascertain any relationship between upregulated USP22 and other members of the
SAGA complex in the development of aggressive PCas. Moreover, in advanced PCas, the coordinated
function of upregulated Myc and USP22 indicates the lack of feedback regulation by hyperactivated Myc.
Therefore, to develop better targeted therapeutic approaches, a comprehensive understanding about the
functional interactions among the various sub-units of SAGA and their relationships with AR/Myc is
important. Moreover, the differential functions of USP22 in the normal prostate, aggressive disease and
disease progression are not fully understood. Thus, defining the role of USP22 will be beneficial for the
development of future therapeutic modalities.

DECLARATIONS
Authors’ contributions
Wrote the paper jointly and SD analyze the data: Nag N, Dutta S

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by grants (1R21CA241234-01) to Dutta S.

Conflicts of interest
Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.