Ube2t, the ubiquitin-conjugating enzyme E2T, plays a crucial role in the ubiquitination process, which is involved in various cellular functions such as protein degradation, DNA repair, and cell cycle regulation. It interacts with different E3 ubiquitin ligases and is associated with multiple signaling pathways like the p53, Akt/β-catenin, and Wnt/β-catenin pathways, and is of great biological importance in cell survival, proliferation, and tumorigenesis [1-10]. Genetically modified mouse models, including knockout (KO) and conditional knockout (CKO) models, have been instrumental in studying Ube2t.

In pancreatic cancer, Ube2t-conditional knockout (CKO) in spontaneous PC mice (KPC) showed a marked survival advantage after gemcitabine treatment. Ube2t levels were positively correlated with gemcitabine resistance. Mechanistically, Ube2t catalyzes RING1-mediated ubiquitination of p53, relieving transcriptional repression of ribonucleotide reductase subunits, promoting pyrimidine biosynthesis, and alleviating replication stress [1]. In hepatocellular carcinoma, knockdown of Ube2t in xenograft tumor models reduced radioresistance. Ube2t-RNF8 complex monoubiquitinated H2AX/γH2AX upon radiation, facilitating CHK1 activation for DNA repair [2]. In glioblastoma, knockdown of Ube2t in LN229 xenograft mouse models suppressed tumor growth. Ube2t induced ubiquitination-mediated degradation of RPL6, promoting malignancy [3]. In breast cancer, Ube2t inhibition in mice suppressed tumor growth by promoting DNA replication stress, cell cycle arrest, and apoptosis [5]. In retinoblastoma, knockdown of Ube2t inhibited subcutaneous tumor growth in vivo, reducing cell viability and increasing apoptosis [4]. In glioblastoma, Ube2t knockdown sensitized cells to temozolomide (TMZ), and in a xenograft mouse model, Ube2t facilitated TMZ resistance by activating the Wnt/β-catenin pathway [6].

In conclusion, model-based research, especially through Ube2t KO/CKO mouse models, has revealed that Ube2t is involved in promoting tumor growth, drug resistance, and radioresistance in multiple cancer types. These findings suggest that targeting Ube2t could be a potential therapeutic strategy for treating pancreatic, liver, brain, breast, and eye cancers, among others.