Page 166 - Read Online

Nag et al. J Cancer Metastasis Treat 2020;6:16 I http://dx.doi.org/10.20517/2394-4722.2020.23 Page 3 of 13

binding factor 1 (TRF1) functions as a negative regulator of telomere length by inhibiting the access of
telomerase to the telomeric region of chromosomes. Poly-ADP-ribosylation of TRF1 by Fbx4 releases it
from the telomere, which in turn gets ubiquitinated and degraded by the proteasomal pathway. On the
contrary, as a part of the SAGA complex, USP22, by deubiqitinating TRF1, restores its protein level and
thereby maintains telomeric length. Depleting USP22 decreases TRF1 levels and enhances cell death by
[27]
genotoxic insults . The deubiquitination activity of USP22 is also important for the stability of Sirtuin
[37]
1 (SIRT1) . By deacetylating, SIRT1 negatively regulates the transcriptional activity of p53 and thereby,
[38]
p53 dependent apoptosis . Deubiquitination also stabilizes another important transcription factor called
c-Myc by the similar SIRT1 mediated pathway. In short, by deubiquitinating a number of transcriptional
regulators such as Hes1, NFAT, COX-2, SNF1, etc., USP22 maintains their homeostatic functions within
the cell [39-42] . A compensatory mechanism also involves SAGA, c-Myc and SIRT1. The enhanced stability of
c-Myc through a USP22 dependent manner increases its transcriptional activity, which in turn, increases
SIRT1 expression. However, the increase in SIRT1 levels enhances its deacetylation activity, which in turn,
[43]
deacetylates USP22 and other SAGA components, thereby decreasing the enzymatic activity of USP22 .
Interestingly, not all deubiquitinations altered protein stability; it also changes the molecular function of
[44]
the protein. Deubiquitinating lysine-63 of FBP1 enhances its recruitment to the chromosome . The role of
USP22 in B cells is also important for its functionality. Complete ablation of USP22 in primary B cells was
found to impair the classical non-homologous end joining and thereby, affects both V(D)J recombination
[45]
and class switch recombination for the development of various IgG and IgE subtypes .
Little is known about USP22 regulation however. Reports indicate that USP22 transcription is
regulated by Sp1 and the PKA/CREB dependent pathway [46,47] . USP22 is also regulated and stabilized by
phosphorylation. Phosphorylation of USP22 at T147 and S237 by CDK1 increases the deubiquitination
status of cyclin B1 in a cell cycle dependent manner. USP22 mediated deubiquitination of Cyclin B1
[48]
promotes its nuclear accumulation and cell cycle progression . USP22 is ubiquitously expressed in
human subjects as well as in mice. In mice, USP22 expression was detected as early as in E4.5. Loss of
both USP22 alleles results in an embryonic lethality starting at E10.5 and no live embryos were recovered
after E14.5. Embryonic expression patterns indicate that the potential functions of USP22 relate to the
development of extra-embryonic tissues and the loss of function of embryonic USP22 fails to establish
vascular interactions with the maternal circulatory system, which leads to immense hypoxic stress induced
lethality. Loss of USP22 is also associated with impairments in transforming growth factor β, vascular
endothelial growth factor receptor-2 and platelet derived growth factor signaling axes in endothelial cells,
and pericytes have been shown to be implicated with detrimental effects on cell survival, differentiation
and vessel formation. However, the heterozygous loss of USP22 in mice is still viable but with retardation
of growth and brain development [38,45] . USP22 expression is also important for embryonic stem cell (ESC)
differentiation into the embryonic body where Sox2 expression needs to be suppressed. Studies have
reported that USP22 functions as a transcriptional repressor by occupying and deubiquitinating H2B at the
Sox2-promoter region during the differentiation of ESC into the embryonic body. USP22 expression is also
[18]
important for regulating neural stem/progenitor cell maintenance through the Notch signaling pathway .
Deubiquitination by USP22 stabilizes the expression of Hes1 protein that negatively modulates neuronal
differentiation. On the contrary, depletion of USP22 delays Hes1 oscillation and thereby, induces neuronal
[39]
differentiation from neuronal progenitor stem cells . Overall, USP22 functions in multiple pathways to
maintain cellular homeostasis and physiological functions of cells.

USP22 EXPRESSION IS FREQUENTLY ALTERED IN CANCER
Altered expression of USP22 was first detected in microarray studies from patient tissue cohorts where
[17]
the expression of 11-gene signatures in stem like cells correlates with poor prognosis of the cancer .
Over the years, upregulation of USP22 has been validated in several cancers such as breast, colorectal,
pancreatic, lung, ovarian, bladder, lymphoma, glioma, mesothelioma, neuroblastoma, etc. [17,31,49-53] . USP22