USP13, an ubiquitin-specific protease, is a deubiquitination (DUB) enzyme. It removes ubiquitin from substrates, preventing their proteasomal degradation. USP13 is involved in numerous cellular processes such as mitochondrial energy metabolism, autophagy, DNA damage response, and endoplasmic reticulum-associated degradation (ERAD) by regulating the deubiquitination of key substrate proteins [1,4]. Dysregulation of USP13 is associated with many diseases, especially malignant tumors [1]. Genetic models, like KO/CKO mouse models, can be valuable for studying its functions.

In a KPU mouse model (KrasG12D/+; Trp53flox/flox background with USP13 overexpression), USP13 was found to drive lung squamous cell carcinoma (LUSC) by altering lineage-determining factors in club cells and reinforcing their fate towards squamous carcinoma development [3]. In ccRCC, depletion of USP13 led to decreased cell proliferation in 2D and 3D assays and reduced tumor growth in vivo, as it promotes the deubiquitination and stability of ZHX2, a protein involved in ccRCC tumorigenesis [2]. In KRAS-mutant NSCLC, USP13 promoted metastasis, and its depletion could potentially be a treatment strategy as 2-methoxyestradiol, an inhibitor of USP13, suppressed metastasis in vitro and in vivo [5]. In GIST cells, inhibition of USP13 in murine xenograft models led to ATG5 decay and enhanced the treatment efficacy of imatinib [6]. In gastric cancer, depletion of USP13 in nude mouse experiments suppressed tumor growth in vivo, as USP13 deubiquitinates and stabilizes cyclin D1 to promote cell cycle progression and proliferation [7]. In lung adenocarcinoma with KRAS mutation, USP13 depletion promoted an autophagy-to-ferroptosis switch in vitro and in xenograft tumor mouse models [8]. In aged Usp13-deficient mice, there was impaired autophagic activity and increased vulnerability to bleomycin-induced fibrosis [9].

In conclusion, USP13 plays essential roles in various biological processes, especially in autophagy, cell cycle regulation, and lineage-determining factor regulation. Model-based research, particularly using KO/CKO mouse models, has revealed its significant contributions to diseases such as lung cancer, kidney cancer, NSCLC, GIST, gastric cancer, and idiopathic pulmonary fibrosis, suggesting that USP13 could be a potential therapeutic target for these diseases.

References:

1. Li, Xiaolong, Yang, Ge, Zhang, Wenyao, Zhao, Qi, Wang, Feng. 2022. USP13: Multiple Functions and Target Inhibition. In Frontiers in cell and developmental biology, 10, 875124. doi:10.3389/fcell.2022.875124. https://pubmed.ncbi.nlm.nih.gov/35445009/

2. Xie, Haibiao, Zhou, Jin, Liu, Xijuan, Gong, Kan, Zhang, Qing. 2022. USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2119854119. doi:10.1073/pnas.2119854119. https://pubmed.ncbi.nlm.nih.gov/36037364/

3. Kwon, Juntae, Zhang, Jinmin, Mok, Boram, Toretsky, Jeffrey, Han, Cecil. 2023. USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity. In Molecular cancer, 22, 204. doi:10.1186/s12943-023-01892-x. https://pubmed.ncbi.nlm.nih.gov/38093367/

4. Wang, Qian, Sun, Zhenzhen, Xia, Weiwei, Zhang, Yue, Jia, Zhanjun. 2022. Role of USP13 in physiology and diseases. In Frontiers in molecular biosciences, 9, 977122. doi:10.3389/fmolb.2022.977122. https://pubmed.ncbi.nlm.nih.gov/36188217/

5. Guo, Yanguan, Tian, Jiaxin, Guo, Yongjian, Hua, Zichun, Chen, Guo. 2023. Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin. In Cell reports, 42, 113511. doi:10.1016/j.celrep.2023.113511. https://pubmed.ncbi.nlm.nih.gov/38043062/

6. Gao, Zhishuang, Li, Chao, Sun, Haoyu, Li, Xueming, Xu, Hao. 2022. N6-methyladenosine-modified USP13 induces pro-survival autophagy and imatinib resistance via regulating the stabilization of autophagy-related protein 5 in gastrointestinal stromal tumors. In Cell death and differentiation, 30, 544-559. doi:10.1038/s41418-022-01107-8. https://pubmed.ncbi.nlm.nih.gov/36528756/

7. Ma, Cunying, Wang, Dandan, Tian, Zhuangfei, Jia, Jihui, Liu, Zhifang. 2023. USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation. In Oncogene, 42, 2249-2262. doi:10.1038/s41388-023-02739-x. https://pubmed.ncbi.nlm.nih.gov/37311811/

8. Chen, Ling, Ning, Jieling, Linghu, Li, Zhang, Bin, Tao, Yongguang. 2024. USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway. In Autophagy, 21, 565-582. doi:10.1080/15548627.2024.2410619. https://pubmed.ncbi.nlm.nih.gov/39360581/

9. Liu, Yuan, Li, Zhen, Xiao, Huijuan, Dai, Huaping, Wang, Chen. . USP13 Deficiency Impairs Autophagy and Facilitates Age-related Lung Fibrosis. In American journal of respiratory cell and molecular biology, 68, 49-61. doi:10.1165/rcmb.2022-0002OC. https://pubmed.ncbi.nlm.nih.gov/36150040/