Ube2t, a ubiquitin-conjugating enzyme E2, is a crucial component of the ubiquitin-proteasome system. It plays a significant role in protein ubiquitination, which is involved in multiple cellular processes such as proliferation, apoptosis, invasion, and metabolism. Through ubiquitination, it influences various signaling pathways, thus being of great biological importance. Genetic models, especially gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying Ube2t [5].

In pancreatic cancer, Ube2t-conditional knockout in spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) showed a marked survival advantage after gemcitabine treatment. Mechanistically, Ube2t catalyzes RING1-mediated ubiquitination of p53, relieving transcriptional repression of ribonucleotide reductase subunits, leading to unrestrained pyrimidine biosynthesis and alleviation of replication stress, conferring gemcitabine resistance [1]. In hepatocellular carcinoma, Ube2t-regulated H2AX monoubiquitination, identified in xenograft tumor models, induced radioresistance by facilitating CHK1 activation, and Ube2t overexpression promoted HCC development in in vitro and in vivo experiments through increasing pyrimidine metabolism by promoting Akt K63-linked ubiquitination [2,3]. In breast cancer, Ube2t inhibition in cell culture and mouse models suppressed tumor growth by promoting DNA replication stress, cell cycle arrest, and apoptosis [4].

In conclusion, Ube2t is essential in regulating multiple cellular processes through protein ubiquitination. KO/CKO mouse models have revealed its roles in various cancer-related biological processes, such as drug resistance, radioresistance, and tumor growth. Understanding Ube2t's functions through these models provides potential therapeutic targets for treating diseases like pancreatic, liver, and breast cancers [1,2,3,4].

References:

1. Jiang, Xiangyan, Ma, Yong, Wang, Tao, Yu, Zeyuan, Jiao, Zuoyi. 2023. Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress. In Gastroenterology, 164, 1232-1247. doi:10.1053/j.gastro.2023.02.025. https://pubmed.ncbi.nlm.nih.gov/36842710/

2. Sun, Jingyuan, Zhu, Zhenru, Li, Wenwen, Liu, Li, Wu, Dehua. 2020. UBE2T-regulated H2AX monoubiquitination induces hepatocellular carcinoma radioresistance by facilitating CHK1 activation. In Journal of experimental & clinical cancer research : CR, 39, 222. doi:10.1186/s13046-020-01734-4. https://pubmed.ncbi.nlm.nih.gov/33087136/

3. Zhu, Zhenru, Cao, Chuanhui, Zhang, Dongyan, Wu, Dehua, Sun, Jingyuan. 2022. UBE2T-mediated Akt ubiquitination and Akt/β-catenin activation promotes hepatocellular carcinoma development by increasing pyrimidine metabolism. In Cell death & disease, 13, 154. doi:10.1038/s41419-022-04596-0. https://pubmed.ncbi.nlm.nih.gov/35169125/

4. Dutta, Roshan, Guruvaiah, Praveen, Reddi, Kiran Kumar, Singh, Kamaljeet, Gupta, Romi. 2022. UBE2T promotes breast cancer tumor growth by suppressing DNA replication stress. In NAR cancer, 4, zcac035. doi:10.1093/narcan/zcac035. https://pubmed.ncbi.nlm.nih.gov/36338541/

5. Gao, Chang, Liu, Yan-Jun, Yu, Jing, Yang, Guan-Jun, Chen, Jiong. 2024. Unraveling the Role of Ubiquitin-Conjugating Enzyme UBE2T in Tumorigenesis: A Comprehensive Review. In Cells, 14, . doi:10.3390/cells14010015. https://pubmed.ncbi.nlm.nih.gov/39791716/