Otub2, short for otubain-2, is a functional cysteine protease in the OTU family with deubiquitinase activity. It is involved in deubiquitination of many key proteins in different cell signaling pathways, such as the PD-1/PD-L1 axis, Hippo-independent YAP/TAZ activation, and regulation of glycolysis. Understanding its function is crucial as it has implications in normal development, physiological function, and disease, especially cancer [4].

Genetic deletion of Otub2 in tumor cells has been studied. In various human cancers, knockout of Otub2 decreases the expression of PD-L1 proteins on the tumor cell surface, making tumor cells more sensitive to CD8+ T-cell-mediated cytotoxicity [1]. In colorectal cancer, Otub2-knockout CRC cells show attenuated proliferation and migration, elevated apoptosis, and increased sensitivity to chemotherapy drugs, as Otub2 normally promotes PKM2 activity and glycolysis [2]. In ovarian cancer, epigenetic silencing of Otub2 drives mitochondrial metabolic reprogramming. Although not a traditional knockout, this silencing promotes tumorigenesis and chemoresistance [3].

In conclusion, Otub2 plays significant roles in regulating multiple biological processes, especially those related to tumorigenesis. Studies using gene-knockout or silencing models have revealed its role in cancer-related pathways such as immune evasion, cell metabolism, and metastasis. These findings suggest that Otub2 could be a potential therapeutic target for cancer treatment.

References:

1. Ren, Wenfeng, Xu, Zilong, Chang, Yating, Huang, Chenghao, Xia, Ningshao. 2024. Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1. In Nature communications, 15, 9. doi:10.1038/s41467-023-44466-7. https://pubmed.ncbi.nlm.nih.gov/38167274/

2. Yu, Shuyu, Zang, Weicheng, Qiu, Yuchong, Liao, Liming, Zheng, Xiaofeng. 2021. Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis. In Oncogene, 41, 46-56. doi:10.1038/s41388-021-02071-2. https://pubmed.ncbi.nlm.nih.gov/34671086/

3. Nan, Yabing, Wu, Xiaowei, Luo, Qingyu, Zhang, Lingqiang, Liu, Zhihua. 2024. OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2315348121. doi:10.1073/pnas.2315348121. https://pubmed.ncbi.nlm.nih.gov/38701117/

4. Li, Jun, Zhang, Na, Li, Meihua, Meng, Wei, Ouyang, Taohui. 2022. The Emerging Role of OTUB2 in Diseases: From Cell Signaling Pathway to Physiological Function. In Frontiers in cell and developmental biology, 10, 820781. doi:10.3389/fcell.2022.820781. https://pubmed.ncbi.nlm.nih.gov/35309903/