Usp15, or Ubiquitin-specific protease 15, is a deubiquitinating enzyme (DUB) that plays a crucial role in the process of protein deubiquitination, maintaining protein stability, and regulating signal pathways [1,4,7]. It is involved in many biological cell processes, such as TLR signaling, RIG-I signaling, NF-κB, and IRF3/IRF7-dependent transcription for cytokine production, as well as pathways related to tumorigenesis like p53 and TGF-β signaling [4]. Genetic models, especially KO/CKO mouse models, can be valuable in further exploring its functions.

In various cancers, Usp15 shows complex roles. In triple-negative breast cancer, it interacts with and deubiquitinates PARP1, promoting its stability, DNA repair, and cell proliferation [2]. In gastric cancer, high expression of Usp15 drives malignant progression through glucose metabolism remodeling by regulating the ubiquitination degradation of HKDC1 [3]. In clear cell renal cell carcinoma, TFAP4-activated Usp15 stabilizes SHC1 via deubiquitination, deteriorating the cancer [8]. However, in pancreatic cancer, in vivo CRISPR screens suggest that Usp15 functions as a tumor suppressor, with loss of Usp15 leading to reduced inflammatory responses and increased sensitivity to PARP inhibition and Gemcitabine [5]. In lung cancer, USP15 negatively regulates cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction, as its knockout in lung cancer cells enhances migration, invasion, and autophagy [6].

In conclusion, Usp15 is a key deubiquitinating enzyme involved in multiple biological processes and disease conditions, especially various cancers. Model-based research, including KO/CKO mouse models, has revealed its complex and context-dependent roles in cancer, either promoting or suppressing tumorigenesis, which provides important insights into understanding disease mechanisms and potential therapeutic strategies.

References:

1. Li, Yan-Chi, Cai, Song-Wang, Shu, Yu-Bin, Chen, Mei-Wan, Shi, Zhi. 2022. USP15 in Cancer and Other Diseases: From Diverse Functionsto Therapeutic Targets. In Biomedicines, 10, . doi:10.3390/biomedicines10020474. https://pubmed.ncbi.nlm.nih.gov/35203682/

2. Sun, Xiaoxiang, Tang, Huanyin, Chen, Yu, Jiang, Ying, Mao, Zhiyong. 2023. Loss of the receptors ER, PR and HER2 promotes USP15-dependent stabilization of PARP1 in triple-negative breast cancer. In Nature cancer, 4, 716-733. doi:10.1038/s43018-023-00535-w. https://pubmed.ncbi.nlm.nih.gov/37012401/

3. Huangfu, Longtao, Zhu, Huanbo, Wang, Gangjian, Ji, Jiafu, Xing, Xiaofang. 2024. The deubiquitinase USP15 drives malignant progression of gastric cancer through glucose metabolism remodeling. In Journal of experimental & clinical cancer research : CR, 43, 235. doi:10.1186/s13046-024-03152-2. https://pubmed.ncbi.nlm.nih.gov/39164728/

4. Georges, Anna, Gros, Philippe, Fodil, Nassima. 2021. USP15: a review of its implication in immune and inflammatory processes and tumor progression. In Genes and immunity, 22, 12-23. doi:10.1038/s41435-021-00125-9. https://pubmed.ncbi.nlm.nih.gov/33824497/

5. Martinez, Sebastien, Wu, Shifei, Geuenich, Michael, Elling, Ulrich, Schramek, Daniel. 2024. In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer. In Nature communications, 15, 5266. doi:10.1038/s41467-024-49450-3. https://pubmed.ncbi.nlm.nih.gov/38902237/

6. Kim, Mi-Jeong, Min, Yoon, Jeong, Soo-Kyung, Chun, Eunyoung, Lee, Ki-Young. 2022. USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction. In Cell death & disease, 13, 348. doi:10.1038/s41419-022-04808-7. https://pubmed.ncbi.nlm.nih.gov/35422093/

7. Das, Tanuza, Song, Eun Joo, Kim, Eunice EunKyeong. 2021. The Multifaceted Roles of USP15 in Signal Transduction. In International journal of molecular sciences, 22, . doi:10.3390/ijms22094728. https://pubmed.ncbi.nlm.nih.gov/33946990/

8. Shi, Yaxing, Zhang, Jing, Li, Jiaxing, Yang, Da, Ju, Lincheng. 2024. USP15, activated by TFAP4 transcriptionally, stabilizes SHC1 via deubiquitination and deteriorates renal cell carcinoma. In Cancer science, 115, 2617-2629. doi:10.1111/cas.16237. https://pubmed.ncbi.nlm.nih.gov/38847328/