Usp7, also known as Herpesvirus associated Ubiquitin-Specific Protease (HAUSP), is a deubiquitinating enzyme (DUB) that plays critical roles in numerous cellular processes, including epigenetics, tumour suppression, oncogenesis, DNA damage response, immunity, and viral infection [2]. It is involved in regulating ubiquitination in genome stability pathways [5]. Genetic models, such as KO/CKO mouse models, can be valuable for studying its functions.

In cancer, Usp7 has been shown to be overexpressed in multiple types, like breast, prostate, colorectal, and lung cancers [1]. In lung cancer, specific silencing of Usp7 using siRNA or inhibitors led to phenotypic and functional changes in M2 tumour-associated macrophages (TAMs), favouring CD8+ T-cell proliferation in vitro and delaying tumour growth in mice [3]. In non-small cell lung cancer (NSCLC), Usp7 directly deubiquitinates and stabilizes KRAS, promoting cell proliferation, and Usp7 inhibitors can suppress NSCLC cell proliferation, especially in cells resistant to the KRAS-G12C inhibitor AMG510 [4]. In triple-negative breast cancers (TNBC), USP7 stabilizes the oncoprotein Forkhead Box M1 (FOXM1) through deubiquitination, and a USP7-specific degrader can suppress tumour growth both in vitro and in vivo in a p53-independent manner [6]. In nasopharyngeal carcinoma, Usp7 stabilizes lysine-specific demethylase 5B (KDM5B), promoting tumour progression and cisplatin resistance, and deletion of Usp7 increases cisplatin sensitivity [7].

In conclusion, Usp7 is a crucial regulator in various biological processes, especially in the context of cancer. Model-based research, particularly through KO/CKO mouse models, has revealed its role in promoting tumour growth, metastasis, and drug resistance in different cancer types. Understanding Usp7 functions can provide potential therapeutic targets for cancer treatment.

References:

1. Saha, Gouranga, Roy, Srija, Basu, Malini, Ghosh, Mrinal K. 2023. USP7 - a crucial regulator of cancer hallmarks. In Biochimica et biophysica acta. Reviews on cancer, 1878, 188903. doi:10.1016/j.bbcan.2023.188903. https://pubmed.ncbi.nlm.nih.gov/37127084/

2. Bojagora, Anna, Saridakis, Vivian. 2020. USP7 manipulation by viral proteins. In Virus research, 286, 198076. doi:10.1016/j.virusres.2020.198076. https://pubmed.ncbi.nlm.nih.gov/32603670/

3. Dai, Xiaomeng, Lu, Lisen, Deng, Suke, Jin, Honglin, Yang, Kunyu. 2020. USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer. In Theranostics, 10, 9332-9347. doi:10.7150/thno.47137. https://pubmed.ncbi.nlm.nih.gov/32802195/

4. Huang, Bin, Cao, Dan, Yuan, Xiao, Tian, Ruijun, Huang, Hao. 2024. USP7 deubiquitinates KRAS and promotes non-small cell lung cancer. In Cell reports, 43, 114917. doi:10.1016/j.celrep.2024.114917. https://pubmed.ncbi.nlm.nih.gov/39499616/

5. Valles, Gabrielle J, Bezsonova, Irina, Woodgate, Roger, Ashton, Nicholas W. 2020. USP7 Is a Master Regulator of Genome Stability. In Frontiers in cell and developmental biology, 8, 717. doi:10.3389/fcell.2020.00717. https://pubmed.ncbi.nlm.nih.gov/32850836/

6. Yi, Jingjie, Li, Huan, Chu, Bo, Jin, Jian, Gu, Wei. 2023. Inhibition of USP7 induces p53-independent tumor growth suppression in triple-negative breast cancers by destabilizing FOXM1. In Cell death and differentiation, 30, 1799-1810. doi:10.1038/s41418-023-01180-7. https://pubmed.ncbi.nlm.nih.gov/37291217/

7. Zhang, Bin, Li, Jie, Wang, Yijun, Li, Yan, Yang, Kunyu. 2024. Deubiquitinase USP7 stabilizes KDM5B and promotes tumor progression and cisplatin resistance in nasopharyngeal carcinoma through the ZBTB16/TOP2A axis. In Cell death and differentiation, 31, 309-321. doi:10.1038/s41418-024-01257-x. https://pubmed.ncbi.nlm.nih.gov/38287116/