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Page 4 of 13 Nag et al. J Cancer Metastasis Treat 2020;6:16 I http://dx.doi.org/10.20517/2394-4722.2020.23

mainly functions as a part of the SAGA complex and depletion of USP22 alters the expression of a variety
[54]
of transcriptional regulators that ultimately affect the cellular conserved pathway or cell metabolism . On
the contrary, overexpression of USP22 often stabilizes the transcriptional effector proteins that directly or
indirectly influence gene expression. Higher expression of USP22 is associated with increased risk of cancer
[19]
recurrence and poor disease-free survival . USP22 expression also correlates with cell cycle progression.
In fact, depletion of USP22 has been shown to be associated with cell cycle arrest, mainly at the G0/G1
phase [18,48,55,56] . Moreover, the depletion of USP22 was shown to decrease in vivo tumor growth [19,55] .

The oncogenic role of USP22 in cancer stem cells (CSC) has been identified as a poor prognostic factor in
multiple cancer models. Mechanistic studies indicate that by deubiquitination, USP22 has been associated
with the stabilization of a variety of its downstream proteins that are important for the development and
maintenance of CSC including BMI1. It has also been shown that the increased stability of BMI1 induces
CSC populations by inducing the expression of stemness associated genes such as CD133, SOX2, OCT4
[57]
and NANOG and thereby, favor the progression of gastric cancer . The role of USP22 and BMI1 in glioma
associated stem cells has also been reported. Under hypoxic conditions, USP22 stabilizes BMI1 to induce
[58]
CSC formation for cancer progression in glioma models .
In non-small cell lung cancer (NSCLC), the upregulation of USP22 was reported to be associated with
[59]
advanced stage or recurrent NSCLC and considered as a poor prognostic marker for overall survival .
Knockdown of USP22 in an in vivo model was shown to decrease tumor angiogenesis, impair non-
homologous DNA damage repair pathways and significantly improve the therapeutic efficacy of cisplatin.
USP22 upregulation affects a broad range of pathways in NSCLC to maintain tumor aggressiveness.
Cisplatin-resistant lung adenocarcinoma cells were shown to be associated with upregulation of USP22.
According to that model, USP22 enhances DNA damage repair and cisplatin resistance by deubiquitinating
histone H2A, which in turn facilitates the phosphorylation of histone H2AX. In addition, USP22 was
shown to decrease the acetylation of Ku70 by stabilizing SIRT11 via deubiquitination. Ku70 acetylation
dissociates the Bax-Ku70 interaction and thereby, induces apoptosis by favoring mitochondrial
translocation of Bax. However, upregulation of USP22 in lung adenocarcinoma inhibits Bax-mediated
[52]
apoptosis in cisplatin-resistant cells . Upregulation of USP22 was also shown to be associated with
[60]
chemotherapy-resistant pancreatic cancer cell survival by enhancing autophagic activity . In breast and
colorectal cancer, upregulation of USP22 was reported to be associated with decreased therapeutic efficacy
of the HSP90 inhibitor ganetespib. Depletion of USP22 in an in vivo model of colorectal cancer was shown
[61]
to increase the therapeutic potentiation of ganetespib .

In gastric cancer, the co-expression of USP22 and BMI1 was shown to be associated with shorter disease-
[62]
free survival and a poor prognosis for overall survival . This was similarly reported in colon cancers. The
upregulated expression of USP22 was significantly correlated with both a decrease in relapse-free survival
and overall survival. An in vitro study showed that the upregulation of USP22 mediated the enhanced
expression of BMI1 and Cyclin D2, and was responsible for increased cell proliferation and the metastatic
[63]
behavior of colon cancer cells . In hepatocellular carcinoma, the enhanced expression of USP22 was
[64]
shown to be an independent factor for a poor prognosis with tumor progression . The enhanced stability
of c-Myc following USP22 mediated deubiquitination was reported to be associated with breast cancer cell
[43]
proliferation and metastatic activity . The upregulation of USP22 was also reported to be associated with a
[66]
[65]
poor prognosis in papillary thyroid carcinoma and glioma . In retinoblastoma, the depletion of USP22
[67]
has been shown to induce cancer cell apoptosis by suppressing the TERT/P53 signal pathway .
In the majority of cancers, USP22 functions like an oncogene. Tumor suppressive functions however,
were also reported in certain cancer models such as acute myeloid leukemia (AML) and colorectal cancer.
Recently, in an in vivo model, it was shown that the deletion of USP22 from Mx1-Cre mice carrying