Usp32-KO Mouse

Usp32, or ubiquitin-specific peptidase 32, is a crucial member of the ubiquitin-specific protease family. It functions as a deubiquitinating enzyme, hydrolyzing ubiquitin molecules from ubiquitin-linked proteins, thus inversely regulating protein degradation and influencing protein function. It is associated with the ubiquitin-proteasome pathway, a vital protein regulatory system in cells. Usp32 is important in various cellular biological processes such as cell cycle progression, proliferation, migration, and invasion [1].

Knockout (KO) of Usp32 in primary hTERT-RPE1 cells leads to hyperubiquitination of LAMTOR1, impairing its interaction with the vacuolar H⁺-ATPase, reducing Ragulator function, and limiting mTORC1 recruitment. This results in decreased mTORC1 activity and induced autophagy [2]. In gastric cancer, knockdown of Usp32 significantly inhibits cell proliferation and migration both in vitro and in vivo, indicating its role as an oncogene [3]. In non-small cell lung cancer, interference with Usp32 inhibits cell proliferation, migration, and EMT development [4]. In hepatocellular carcinoma, knockdown of Usp32 represses cell proliferation, colony formation, and migration in vitro and inhibits tumor growth in vivo [5]. In gastrointestinal stromal tumours, loss of Rab35, which is regulated by Usp32, decreases exosome secretion and hampers the transmission of imatinib resistance [6]. In colorectal carcinoma, wet experiments confirm that Usp32 is critical for cell proliferation, survival, and migration as well as tumour growth [7].

In summary, Usp32 plays essential roles in multiple biological processes, especially in cell growth, migration, and autophagy regulation. Model-based research, particularly Usp32 KO experiments, has revealed its significant contributions to various cancer-related processes, making it a potential therapeutic target for cancers such as gastric, lung, liver, gastrointestinal stromal, and colorectal cancers.

References:

1. Li, Shuang, Song, Yang, Wang, Kexin, Liu, Chunyan, Li, Bing. 2023. USP32 deubiquitinase: cellular functions, regulatory mechanisms, and potential as a cancer therapy target. In Cell death discovery, 9, 338. doi:10.1038/s41420-023-01629-1. https://pubmed.ncbi.nlm.nih.gov/37679322/

2. Hertel, Alexandra, Alves, Ludovico Martins, Dutz, Henrik, Steinberg, Florian, Bremm, Anja. . USP32-regulated LAMTOR1 ubiquitination impacts mTORC1 activation and autophagy induction. In Cell reports, 41, 111653. doi:10.1016/j.celrep.2022.111653. https://pubmed.ncbi.nlm.nih.gov/36476874/

3. Dou, Ning, Hu, Qingqing, Li, Li, Li, Yandong, Gao, Yong. 2020. USP32 promotes tumorigenesis and chemoresistance in gastric carcinoma via upregulation of SMAD2. In International journal of biological sciences, 16, 1648-1657. doi:10.7150/ijbs.43117. https://pubmed.ncbi.nlm.nih.gov/32226309/

4. Li, Shuang, Yang, Lina, Ding, Xiaoyan, Li, Bing, Liu, Chunyan. 2024. USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway. In Oncogenesis, 13, 27. doi:10.1038/s41389-024-00528-z. https://pubmed.ncbi.nlm.nih.gov/39030175/

5. Xiu, Mengxi, Bao, Wenfang, Wang, Jialin, Li, Yandong, Hai, Yanan. 2023. High USP32 expression contributes to cancer progression and is correlated with immune infiltrates in hepatocellular carcinoma. In BMC cancer, 23, 1105. doi:10.1186/s12885-023-11617-4. https://pubmed.ncbi.nlm.nih.gov/37957631/

6. Li, Chao, Gao, Zhishuang, Cui, Zhiwei, Xu, Zekuan, Xu, Hao. 2023. Deubiquitylation of Rab35 by USP32 promotes the transmission of imatinib resistance by enhancing exosome secretion in gastrointestinal stromal tumours. In Oncogene, 42, 894-910. doi:10.1038/s41388-023-02600-1. https://pubmed.ncbi.nlm.nih.gov/36725886/

7. Duan, Xiaofan, Yeerkenbieke, Gaoshaer, Huang, Siping, Feng, Yanjun. . USP32 Promotes Colorectal Carcinoma Progression Through Activating NF-κB Signalling Pathway. In Journal of cellular and molecular medicine, 29, e70457. doi:10.1111/jcmm.70457. https://pubmed.ncbi.nlm.nih.gov/40122703/