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Gene & Protein in Disease Structure and function of USP7

induces tumorigenesis and chemoresistance [159] . On the activity could serve as a potential clinical treatment
other hand, USP7 stabilizes thyroid hormone receptor- strategy for hematological disease.
interacting protein 12, which subsequently induces the
polyubiquitination of p14(ARF), inactivate p14(ARF), and 7. Development of USP7-specific inhibitors
lastly promotes HCC progression [160] . The above studies Given the diverse roles of USP7 in various diseases, USP7
corroborate USP7 as the novel potential therapeutic target has been widely believed to be an ideal therapeutic target,
for HCC treatment. and many inhibitors against USP7 have been developed. The

Hematological malignancies are usually caused by structural characteristic of USP7 has been described earlier
uncontrolled cell proliferation. MM is a cancer of blood in this article. The TRAF-like domain of USP7 is important
plasma cells with high incidence and mortality rates, and for substrate binding. According to the role of TRAF domain
currently there is no effective treatment strategy. MafB/c- in USP7, researchers have found the first inhibitor of USP7
Maf are highly expressed in several myeloma cell lines, such through high-throughput screening (Table 3). Studies have
as RPMI-8226 and LP1, and they are critical transcription revealed that HBX41108 disrupts the interaction between
factors in myelomagenesis, promoting the cell growth, USP7 and HDM2, which inhibits USP7 deubiquitinating
proliferation, metastasis, and cell cycle progression [161] . activity and fails to stabilize HDM2 protein, thereby
USP7 has been shown to participate in MM progression inducing p53 accumulation and resulting in cell cycle arrest
by increasing the stabilization of MafB/c-Maf proteins. In and apoptosis in tumor cells [162] . Since USP7 belongs to the
addition, CML is a clonal malignancy of hematopoietic Cys protease family, which are highly conserved in terms
stem cells, featured with fusion protein kinase BCR-ABL. of the structural composition, such as USP5, USP8, USP10
It has been demonstrated that deubiquitinase USP7 binds and CYLD, it has been demonstrated that both of their
to BCR-ABL and reduces its polyubiquitination, thereby activity can be inhibited by HBX41108 [163,164] , suggesting
protecting it from degradation and inducing CML cell that the inhibition effect of HBX41108 on USP7 activity is
proliferation . Therefore, inhibition of USP7 kinase not specific enough and further research is needed.
[38]
Table 3. The chemical structure of USP7 inhibitors, their validated targets, their effect on cell level and tumor model growth

Name Structural formula Validated targets Functional In vitro cell suppression Ref
consequence
HBX 41108 ↓MDM2↑p53; p21 Cell cycle arrest Colon cancer cells [162]
Apotosis

HBX 19818 ↓MDM2↑p53; p21 Cell cycle arrest Colon cancer cells [164]
Apoptosis
Growth inhibition

P22077 ↓MDM2; claspin; Growth inhibition Colon cancer cells; [67,159,165-167]
Pchk1; DDB1; Apotosis Neuroblastoma cells;
TIP60↑p53; p21; Hepatocellular cells;
Cle-Caspase-3 Lung cancer cells
P5091 ↓MDM2; MDMX; Cell cycle arrest Colon cancer cells; [18,20,52,161,168]
MafB; c-Maf; BCR-ABL; Apotosis Neuroblastoma cells;
EZH2↑p53; p21 Autophagy Hepatocellular cells;
growth inhibition Glioblastoma cells;
Prostate cancer cells;
Ovarian cancer cells
Multiple myeloma cells
Morin ↓ Prickle1, mTORC2 Cell migration Rheumatoid arthritis cells [169]
inhibition

I3MO ↓ NEK2, PA28γ, PA200 Apotosis Multiple myeloma cells [170]
NF-κB signaling DNA damage
Cell cycle arrest

Volume 1 Issue 2 (2022) 8 https://doi.org/10.36922/gpd.v1i2.118