Pan-Cancer Analyses of the Tumor Microenvironment Reveal That Ubiquitin-Conjugating Enzyme E2C Might Be a Potential Immunotherapy Target

Increasing evidence indicated that the tumor microenvironment (TME) played a crucial role in cancer initiation and progression. Ubiquitin-conjugating enzyme E2C (UBE2C) was differentially expressed in many cancer types. However, the immunological and prognostic roles of UBE2C were unclear. Differentially expressed genes (DEGs) of 29 cancer types were downloaded from GEPIA2 and 4 cancer types failed to download owing to no DEGs. Furthermore, the gene expression profiles, mutation data, and survival data of 33 cancer types were obtained from UCSC Xena. Clinical stage relevance, tumor mutational burden (TMB), TME relevance analysis, and gene set enrichment analysis (GSEA) of DEGs in 33 cancer types were performed. And DEGs were identified in oral squamous cell carcinoma (OSCC) by biological experiments. Previous studies indicated that UBE2C was related to the prognosis of many cancers. In our study, the higher UBE2C expression level meant a terminal clinical stage in 8 cancer types and the expression level of UBE2C was related to TMB in 20 cancer types. In addition, both immune relevance analysis and GSEA showed that UBE2C might participate in immune response in many cancers. Furthermore, the UBE2C mRNA level and protein level were all identified as upregulated in OSCC cell lines and tissues. UBE2C was differentially expressed in many cancer types and related to the pathogenesis and TME of many cancers, which might be a potential diagnostic and therapeutic biomarker.

UBE2S promotes cell chemoresistance through PTEN-AKT signaling in hepatocellular carcinoma

Ubiquitination displays a crucial role in various biological functions, such as protein degradation, signal transduction, and cellular homeostasis. Accumulating evidence has indicated that ubiquitination is essential in cancer progression. Ubiquitin-conjugating enzyme E2S (UBE2S) is a member of ubiquitin-conjugating enzyme family of the ubiquitin system and its role in hepatocellular cancer (HCC) is largely unknown. We investigated the role of UBE2S in HCC and found UBE2S upregulation is relevant with large tumor size, recurrence, and advanced TNM stage, serving as an independent risk factor of overall survival (OS) and disease-free survival (DFS) for HCC patients. We conducted in vitro experiments and found that in HCC cells, UBE2S overexpression increases the resistance to 5-FU and oxaliplatin, while UBE2S knockdown achieves an opposite effect. UBE2S is transcriptionally activated by the binding of FOXM1 to UBE2S promoter, which induces its upregulation and reduces PTEN protein level by promoting PTEN ubiquitination at Lys60 and Lys327 and facilitating AKT phosphorylation. The promotional effect of FOXM1-UBE2S axis on HCC cell chemoresistance is attenuated by allosteric AKT inhibitor, MK2206. In conclusion, our results reveal that UBE2S is a prognostic biomarker for HCC patients, and the FOXM1-UBE2S-PTEN-p-AKT signaling axis might be a promising target for the treatment of HCC.

Deletion of Plasmodium falciparum ubc13 increases parasite sensitivity to the mutagen, methyl methanesulfonate and dihydroartemisinin

The inducible Di-Cre system was used to delete the putative ubiquitin-conjugating enzyme 13 gene (ubc13) of Plasmodium falciparum to study its role in ubiquitylation and the functional consequence during the parasite asexual blood stage. Deletion resulted in a significant reduction of parasite growth in vitro, reduced ubiquitylation of the Lys63 residue of ubiquitin attached to protein substrates, and an increased sensitivity of the parasite to both the mutagen, methyl methanesulfonate and the antimalarial drug dihydroartemisinin (DHA), but not chloroquine. The parasite was also sensitive to the UBC13 inhibitor NSC697923. The data suggest that this gene does code for an ubiquitin conjugating enzyme responsible for K63 ubiquitylation, which is important in DNA repair pathways as was previously demonstrated in other organisms. The increased parasite sensitivity to DHA in the absence of ubc13 function indicates that DHA may act primarily through this pathway and that inhibitors of UBC13 may both enhance the efficacy of this antimalarial drug and directly inhibit parasite growth.

Role of Ubiquitin-Conjugating Enzyme UBE2C in Gastrointestinal Cancers

Ubiquitin-conjugating enzyme UBE2C is one of the important members of ubiquitin-proteasome pathway (UPP). Amplification and/or overexpression of UBE2C have been reported in many malignancies, and a high expression of UBE2C is associated with poor clinical outcomes. In this review, the pathological role of dysregulated UBE2C in gastrointestinal cancers and its potential role as a diagnostic and/or a prognostic marker as well as a therapeutic target in these cancers are discussed.