Usp21, short for ubiquitin-specific protease 21, is a member of the ubiquitin-specific protease family, which belongs to the largest subfamily of deubiquitylating enzymes (DUBs). DUBs antagonize ubiquitination by removing ubiquitin from substrates, and Usp21 is involved in various cellular processes such as apoptosis, DNA repair, and signal transduction [2,4].

In cholangiocarcinoma (CCA), Usp21 is upregulated and associated with poor prognosis. It promotes CCA growth and aerobic glycolysis by deubiquitinating and stabilizing HSP90 and ENO1. The stabilization of HSP90 increases HIF1A expression, upregulating key glycolytic enzyme genes [1]. In esophageal squamous cell carcinoma (ESCC), aberrant upregulation of Usp21 accelerates proliferation and metastasis in a deubiquitinase-dependent manner. It binds to, deubiquitinates, and stabilizes G3BP1, activating the Wnt/β-Catenin signaling pathway [3]. In pancreatic cancer, Usp21 promotes KRAS-independent tumor growth by regulating MARK3-induced macropinocytosis, which maintains intracellular amino acid levels for anabolic growth [5].

In summary, Usp21 plays crucial roles in multiple cancers, including CCA, ESCC, and pancreatic cancer, mainly through its deubiquitination function to regulate protein stability and activate related signaling pathways. Research on Usp21 using in vivo models like those in cancer studies helps to understand its functions in disease development, providing potential therapeutic targets for these diseases.

References:

1. Xu, Xiao, Chen, Yananlan, Shao, Shenye, Li, Changxian, Li, Xiangcheng. 2024. USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma. In International journal of biological sciences, 20, 1492-1508. doi:10.7150/ijbs.90774. https://pubmed.ncbi.nlm.nih.gov/38385089/

2. An, Tao, Lu, Yanting, Yan, Xu, Hou, Jingjing. 2022. Insights Into the Properties, Biological Functions, and Regulation of USP21. In Frontiers in pharmacology, 13, 944089. doi:10.3389/fphar.2022.944089. https://pubmed.ncbi.nlm.nih.gov/35846989/

3. Guo, Jiazhong, Zhao, Yunpeng, Sui, Huacong, Li, Peichao, Zhao, Xiaogang. 2024. USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling. In Oncogenesis, 13, 23. doi:10.1038/s41389-024-00524-3. https://pubmed.ncbi.nlm.nih.gov/38906857/

4. Shi, Zhen-Yuan, Li, Chang-Yun, Chen, Ru-Yi, Yang, Guan-Jun, Chen, Jiong. 2024. The emerging role of deubiquitylating enzyme USP21 as a potential therapeutic target in cancer. In Bioorganic chemistry, 147, 107400. doi:10.1016/j.bioorg.2024.107400. https://pubmed.ncbi.nlm.nih.gov/38688196/

5. Hou, Pingping, Ma, Xingdi, Yang, Zecheng, Wang, Y Alan, DePinho, Ronald A. 2021. USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer. In Genes & development, 35, 1327-1332. doi:10.1101/gad.348787.121. https://pubmed.ncbi.nlm.nih.gov/34531315/