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Gene & Protein in Disease Structure and function of USP7

In addition, CD plays a key role in cleaving polyubiquitin In summary, exploring the potential inhibitors against
chains, especially the Cys223 residue, which is essential for USP7 can provide a novel therapeutic strategy in tumor
the deubiquitinase activity of USP7. Using biochemical treatment.
assays and activity-based protein profiling in living systems,
HBX19818 and HBX28258 were found to be catalytic 8. Conclusions
activity inhibitors of USP7, which can selectively inhibit Ubiquitination and deubiquitination are two opposite
the USP7 deubiquitinase activity by binding to its catalytic biological processes, which work together to regulate the
active site [165] (Table 3). In addition, these two compounds post-translational modification of proteins. Various biological
have a higher selectivity to USP7, and have been shown functions of USP7 have been discovered, including its role
to decrease its downstream proteins, leading to cell cycle as a vital regulator of transcription , nuclear export ,
[10]
[20]
arrest and growth inhibition in several tumor cells [164] . inflammatory responses , DNA damage repair ,
[11]
[57]
[54]
Two new compounds, P22077 and P5091, which were antiviral responses , and induction of cell apoptosis [20,171] .
discovered through a high-throughput screen, have been Furthermore, USP7 is considered a cancer-promoting protein
shown to selectively inhibit USP7 activity [161,165] . P22077 in a variety of tumors, including lung cancer, prostate cancer,
HCC, as well MM. The progression of all the above diseases
can activate p53 and its downstream protein p21 in human can be related to the substrate proteins of USP7. USP7 binds
colon carcinoma cells. Further studies found that P22077 to its substrates and stabilizes their proteins or maintains
stabilizes p53 by inducing the degradation of HDM2 .
[57]
their activity, thereby inducing abnormal cell proliferation
P5091, the most recognized inhibitor against USP7 and tumor development. Moreover, studies have uncovered
activity, has been identified to induce MM cell apoptosis that USP7 interacts with HDM2, which is a critical negative
and inhibit xenograft tumor growth. Mechanistically, regulator of p53, to stabilize its protein level . Contrary to the
[24]
P5091 leads to the decrease of HDM2, and subsequently oncogenic role of USP7, several studies have found that it has
stabilizes p53 and p21 in tumor cells by inhibiting USP7 dual function in cancer development. For example, in colon
activity. Interestingly, when MM cell line KMS11 was carcinoma, USP7 inhibits cell proliferation in vitro and tumor
treated with P5091, there was no obvious increase of p53, growth in vivo in the presence of stress due to the constitutive
suggesting that p53 is dispensable for the cytotoxicity expression level of p53 protein [172] . Therefore, further studies
of P5091 . It’s worth pointing out that P5091 shows are required to better understand the role of USP7 in tumors.
[57]
high specificity without affecting other protease activity, More remarkably, in recent years, accumulating research has
except for USP7 [161] . These findings suggest that the USP7 focused on designing small molecule inhibitors of USP7,
inhibitors have potential value in clinical therapy. mainly based on its physical structure or enzyme activity, to
provide potential strategies for cancer treatment. However, the
Recent studies have found that Morin (3, 5, 7, 2’, premise is we need to fully understand the role or mechanism
4’-pentahydroxyflavone), an anti-arthritis compound of USP7 in tumor development, since USP7 stabilizes p53 and
that is present in foods of plant origin, suppresses the its function is unclear in the presence of stress or radiation
pathological migration of fibroblast-like synoviocytes, damage [172] . The diversity of USP7 substrates determines the
and prevents focal adhesion turnover [169] . A molecular complexity of its function in different diseases and tumors, and
operating environment software has been used to show the complications of diseases bring new challenges for USP7
that Morin could bind closely to His461, Met292, and as a target in cancer therapy. Therefore, further investigation
Phe409 amino acid residues in the CD of USP7 through is required to evaluate the benefits and adverse effects of
hydrogen bonds, thus hindering the rotation of the Phe409 inhibiting the enzymatic activity of USP7. In addition, with the
side chain and subsequently inhibiting the binding of USP7 emergence of new molecular tools and in-depth exploration
and substrate Ub. Further, USP7 protects Prickle1 from of USP7 substrates and different strategies to modulate USP7
degradation, and this process can be reversed by Morin to activity, the therapeutic potential of USP7 in diseases will be
block FLS migration. further evaluated.
Furthermore, indirubin-3’-monoxime (I3MO), is one Acknowledgments
of the derivatives of indirubin. The previous study has
reported that the anti-MM activity of I3MO in both drug- None.
sensitive and drug-resistant MM cells by sensitizing MM
cells to bortezomib-induced apoptosis [170] . In return, I3MO Funding
suppresses the growth of MM cells via down-regulating This study was supported by Guangzhou Medical University
the USP7 expression, inducing NEK2 degradation, and Discipline Construction Funds (Basic Medicine) (Grant
suppressing NF-κB signaling in MM. No. JCXKJS2022A05).

Volume 1 Issue 2 (2022) 9 https://doi.org/10.36922/gpd.v1i2.118