• UBE2T
• ubiquitin-conjugating enzyme
• ubiquitin-proteasome system

• Humans
• Ubiquitin-Conjugating Enzymes/metabolism
• Ubiquitin-Conjugating Enzymes/genetics
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Carcinogenesis/metabolism
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasms/enzymology
• Animals
• Signal Transduction
• Ubiquitination

• LY19H160010 Natural Science Foundation of Zhejiang Province

• Biomarker
• Lung adenocarcinoma
• UBE2C
• p53/p21 signaling pathway

• SORBS3
• UBE2T
• lung adenocarcinoma
• ubiquitination

• Animals
• Female
• Humans
• Male
• Mice
• Adenocarcinoma of Lung/metabolism
• Adenocarcinoma of Lung/pathology
• Adenocarcinoma of Lung/genetics
• Cell Line, Tumor
• Cell Proliferation
• Disease Progression
• Interleukin-6/metabolism
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Lung Neoplasms/genetics
• Mice, Inbred BALB C
• Mice, Nude
• Signal Transduction
• STAT3 Transcription Factor/metabolism
• Ubiquitin-Conjugating Enzymes/metabolism
• Ubiquitin-Conjugating Enzymes/genetics
• Ubiquitination
• Adaptor Proteins, Signal Transducing/metabolism
• Muscle Proteins/metabolism

• Chromatin remodelers
• H2A
• H2B
• Histone monoubiquitination
• Transcription initiation
• Ubiquitination

• Histones/genetics
• Histones/metabolism
• Chromatin/genetics
• Nucleosomes/genetics
• Euchromatin
• Heterochromatin
• Ubiquitin/genetics
• Ubiquitin/metabolism
• Ubiquitination
• Transcription Factors/genetics
• Gene Expression

• UBE2T
• drug design
• fragment-based drug discovery
• protein structure
• ubiquitylation

• Ubiquitin-Conjugating Enzymes/metabolism
• Ubiquitin
• Binding Sites

• Hepatocellular carcinoma
• Tumor microenvironment
• Ubiquitin-ligating enzymes
• Ubiquitination

• Humans
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology
• Prospective Studies
• Ubiquitination
• Protein Processing, Post-Translational
• Tumor Microenvironment

• Nanodrug delivery
• Ovarian cancer
• Platinum resistance
• circRNA NUP50
• p53

• Animals
• Humans
• Female
• Cisplatin/pharmacology
• Cisplatin/therapeutic use
• MicroRNAs/metabolism
• RNA, Circular/genetics
• RNA, Circular/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• DNA Helicases/genetics
• DNA Helicases/metabolism
• Cell Line, Tumor
• Poly-ADP-Ribose Binding Proteins/genetics
• Poly-ADP-Ribose Binding Proteins/metabolism
• RNA Helicases/genetics
• RNA Helicases/metabolism
• RNA Helicases/therapeutic use
• RNA Recognition Motif Proteins/genetics
• RNA Recognition Motif Proteins/metabolism
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Ubiquitination
• Cell Proliferation
• Drug Resistance, Neoplasm
• Ubiquitin-Conjugating Enzymes

• 82172652 National Natural Science Foundation of China
• 2016YFC1303700 National Key Research and Development Program of China

• Covalent inhibitor
• Drug discovery
• Fanconi anemia
• Structure
• UBE2T

• Ubiquitin/metabolism
• Cysteine/metabolism
• Ubiquitin-Conjugating Enzymes/metabolism
• Ubiquitination
• High-Throughput Screening Assays

• Autophagy
• Epithelial OC
• Platinum resistance
• Ubiquitin-conjugating enzyme E2S

• Animals
• Mice
• Humans
• Female
• Cisplatin/pharmacology
• Cisplatin/therapeutic use
• Proto-Oncogene Proteins c-akt/metabolism
• Phosphatidylinositol 3-Kinases/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Mice, Nude
• Cell Line, Tumor
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/metabolism
• Signal Transduction
• TOR Serine-Threonine Kinases/metabolism
• Autophagy/genetics
• Cell Proliferation/genetics
• Drug Resistance, Neoplasm/genetics

• BS20230104 PhD research startup foundation of the Third Affiliated Hospital of Zhengzhou University
• No. 82073239 National Natural Science Foundation of China

• bioinformatics analysis
• pan-cancer
• prognostic value
• tumor-associated macrophages
• ubiquitin-conjugating enzyme E2S

• Humans
• Databases, Factual
• Genetic Therapy
• Neoplasms/diagnosis
• Neoplasms/genetics
• Neoplasms/therapy
• Tumor Microenvironment/genetics
• Tumor-Associated Macrophages

• BS20230104 PhD research startup foundation of the Third Affiliated Hospital of Zhengzhou University

• deubiquitination
• gene expression
• myelodysplastic neoplasm
• ubiquitination

• Humans
• Ubiquitin-Specific Peptidase 7/genetics
• Neoplasms
• Myelodysplastic Syndromes/pathology
• Chromosome Aberrations
• Ubiquitination
• Ubiquitin-Conjugating Enzymes/genetics
• Ubiquitin-Conjugating Enzymes/metabolism
• Ubiquitin-Specific Proteases/genetics
• Ubiquitin-Specific Proteases/metabolism

• Acute liver injury
• MG-132
• Oxidative stress
• TLR4/NF-κB pathway

• FBXO43
• HCC
• UBE2C
• m6A modification
• p53

Ubiquitin-binding enzyme E2T (UBE2T), a member of the E2 family of the ubiquitin–proteasome pathway, is associated with tumorigenesis of varioustumours; however, its role and mechanism in ovarian cancer remain unclear.

Our study revealed that UBE2T is highly expressed in ovarian cancer; this high expression was closely related to poor prognosis. Immunohistochemistry was used to validate the high expression of UBE2T in ovarian cancer. This is the first study to demonstrate that UBE2T expression is higher in ovarian cancer with BRCA mutation. Moreover, we demonstrated that UBE2T gene silencing significantly inhibited ovarian cancer cell proliferation and invasion. The epithelial–mesenchymal transition (EMT) of ovarian cancer cells and phosphatidylinositol 3 kinase/protein kinase B (PI3K-AKT) pathway were significantly inhibited. Adding the mechanistic target of rapamycin activator MHY1485 activated the PI3K-AKT pathway and significantly restored the proliferative and invasive ability of ovarian cancer cells. Furthermore, a tumorigenesis experiment in nude mice revealed that tumour growth on mice body surface and tumour tissue EMT were significantly inhibited after UBE2T gene silencing.

This study demonstrated that UBE2T regulates EMT via the PI3K-AKT pathway and plays a carcinogenic role in ovarian cancer. Moreover, UBE2T may interact with BRCA to affect ovarian cancer occurrence and development. Hence, UBE2T may be a valuable novel biomarker for the early diagnosis and prognosis and treatment of ovarian cancer. Further, UBE2T inhibition may be effective for treating ovarian cancer.

The online version contains supplementary material available at 10.1186/s13048-022-01034-9.

• Hepatocellular carcinoma
• UBE2T
• circ_0000291
• miR-1322

The extensive spatial genomic intratumor heterogeneity (ITH) in liver cancer hindered treatment development and limited biomarker design. Early events that drive tumor malignant transformation in tumor founder cells are clonally present in all tumor cell populations, which provide stable biomarkers for the localization of tumor cells and patients’ prognosis. In the present study, we identified the recurrently clonal somatic mutations and copy number alterations (CNAs) (893 clonal somatic mutations and 6,617 clonal CNAs) in 353 liver cancer patients from The Cancer Genome Atlas (TCGA) and evaluated their prognosis potential. We showed that prognosis-related clonal alterations might play essential roles in tumor evolution. We identified 32 prognosis related clonal alterations differentially expressed between paired normal and tumor samples, that their expression was cross-validated by three independent cohorts (50 paired samples in TCGA, 149 paired samples in GSE76297, and 9 paired samples in SUB6779164). These clonal expression alterations were also significantly correlated with clinical phenotypes. Using stepwise regression, we identified five (UCK2, EFNA4, KPAN2, UBE2T, and KIF14) and six (MCM10, UCK2, IQGAP3, EFNA4, UBE2T, and KPNA2) clonal expression alterations for recurrence and survival model construction, respectively. Furthermore, in 10 random repetitions, we showed strong applicability of the multivariate Cox regression models constructed based on the clonal expression genes, which significantly predicted the outcomes of the patients in all the training and validation sets. Taken together, our work may provide a new avenue to overcome spatial ITH and refine biomarker design across cancer types.

Fanconi anemia complementation group I (FANCI) is a critical protein for maintaining DNA stability. However, the exact role of FANCI in tumors remains to be elucidated. The present study aimed to explore the role and potential mechanism of action of FANCI in non-small cell lung cancer (NSCLC). To quantify the expression levels of FANCI and ubiquitin-conjugating enzyme E2T (UBE2T) in NSCLC tissues, reverse-transcription quantitative PCR and western blotting were employed. Cell Counting Kit-8, wound healing and Transwell assays along with flow cytometry analysis and tumor xenograft were used to investigate the biological effects of FANCI in NSCLC in vitro and in vivo. The binding of FANCI with UBE2T was confirmed using a co-immunoprecipitation assay. Epithelial-to-mesenchymal transition (EMT) protein markers were quantified via western blotting. The results showed that FANCI expression level was higher in NSCLC tumor tissues, compared with adjacent tissues. In A549 and H1299 cells, knockdown of FANCI inhibited cell proliferation, migration, invasion, cell cycle and EMT in vitro. Tumor growth was repressed in vitro, upon downregulation of FANCI expression. UBE2T was observed to directly bind to FANCI and regulate its monoubiquitination. Overexpression of UBE2T reversed the effects induced by FANCI knockdown in NSCLC cells. Furthermore, it was noted that FANCI interacted with WD repeat domain 48 (WDR48). Overexpression of WDR48 reversed the effects of FANCI on cell proliferation, migration and EMT. In conclusion, FANCI was identified to be a putative oncogene in NSCLC, wherein FANCI was monouniubiquitinated by UBE2T to regulate cell growth, migration and EMT through WDR48. The findings suggested that FANCI could be used as a prognostic biomarker and therapeutic target for NSCLC.

• Fanconi anemia complementation group I
• epithelial‑mesenchymal transition
• monoubiquitination
• non‑small cell lung cancer
• ubiquitin‑conjugating enzyme E2T

• E2F5
• Gastric cancer
• Proliferation and invasion
• Transcriptional regulation
• UBE2T

Ovarian cancer is one of the important factors that seriously threaten women's health and its morbidity and mortality ranks eighth among female cancers in the world. It is critical to identify potential and promising biomarkers for prognostic evaluation and molecular therapy of OV. Ubiquitin-conjugating enzyme E2S (UBE2S), a potential oncogene, regulates the malignant progression of various tumors; however, its role in OV is still unclear.

The expression and prognostic significance of UBE2S at the pan-cancer level were investigated through high-throughput gene expression analysis and clinical prognostic data from TCGA, GEPIA, and GEO databases. 181 patients with OV were included in this study. Cell culture and cell transfection were performed on OV cell lines (SKOV3 and A2780) and a normal ovarian cell line (IOSE80). The expression level and prognostic significance of UBE2S in OV were verified by western blot, immunohistochemistry, and Kaplan–Meier survival analysis. Through cell transfection, CCK-8, Ki-67 immunofluorescence, wound healing, Transwell, clonogenic, and flow cytometry assays, the effect and detailed mechanism of UBE2S knockdown on the malignant biological behavior of OV cells were explored.

UBE2S exhibited abnormally high expression at the pan-cancer level. The results of RT-qPCR and Western blotting indicated that UBE2S was significantly overexpressed in ovarian cancer cell lines compared with normal cell lines (P < 0.05). Kaplan–Meier survival analysis and Immunohistochemistry indicated that overexpression of UBE2S was related to poor prognosis of OV (HR > 1, P < 0.05). Results of in vitro experiments indicated that UBE2S gene knockdown might inhibit the proliferation, invasion, and prognosis of OV cells by inhibiting the PI3K/AKT/mTOR signaling pathway, thereby blocking the cell cycle and promoting apoptosis (P < 0.05).

UBE2S is a potential oncogene strongly associated with a poor prognosis of OV patients. Knockdown of UBE2S could block the cell cycle and promote apoptosis by inhibiting the PI3K/AKT/mTOR pathway and ultimately inhibit the proliferation, migration and prognosis of ovarian cancer, which suggested that UBE2S might be used for molecular therapy and prognostic evaluation of ovarian cancer.

The online version contains supplementary material available at 10.1186/s10020-022-00489-2.

• Apoptosis
• Cell cycle
• Malignant biological behavior
• Ovarian cancer
• PI3K/AKT/mTOR signaling pathway
• Prognosis
• Ubiquitin-conjugating enzyme E2S

• Biomarker
• Diagnostic
• Hepatocellular carcinoma
• Prognostics
• TP53 mutant
• UBE2C
• UBE2S
• UBE2T
• Ubiquitin-conjugating enzyme 2

Although more pathologic stage-I lung adenocarcinoma (LUAD) was diagnosed recently, some relapsed or distantly metastasized shortly after radical resection. The study aimed to identify biomarkers predicting prognosis in the pathologic stage-I LUAD and improve the understanding of the mechanisms involved in tumorigenesis.

We obtained the expression profiling data for non-small cell lung cancer (NSCLC) patients from the NCBI-GEO database. Differentially expressed genes (DEGs) between early-stage NSCLC and normal lung tissue were determined. After function enrichment analyses on DEGs, the protein-protein interaction (PPI) network was built and analyzed with the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. Overall survival (OS) and mRNA levels of genes were performed with Kaplan–Meier analysis and Gene Expression Profiling Interactive Analysis (GEPIA). qPCR and western blot analysis of hub genes in stage-I LUAD patients validated the significant genes with poor prognosis.

A total of 172 DEGs were identified, which were mainly enriched in terms related to management of extracellular matrix (ECM), receptor signaling pathway, cell adhesion, activity of endopeptidase, and receptor. The PPI network identified 11 upregulated hub genes that were significantly associated with OS in NSCLC and highly expressed in NSCLC tissues compared with normal tissues by GEPIA. Elevated expression of ANLN, EXO1, KIAA0101, RRM2, TOP2A, and UBE2T were identified as potential risk factors in pathologic stage-I LUAD. Except for ANLN and KIAA0101, the hub genes mRNA levels were higher in tumors compared with adjacent non-cancerous samples in the qPCR analysis. The hub genes protein levels were also overexpressed in tumors. In vitro experiments showed that knockdown of UBE2T in LUAD cell lines could inhibit cell proliferation and cycle progression.

The DEGs can probably be used as potential predictors for stage-I LUAD worse prognosis and UBE2T may be a potential tumor promoter and target for treatment.

• AKT/mTOR
• Ovarian cancer
• autophagy
• epithelial–mesenchymal transition (EMT)
• ubiquitin-conjugating enzyme E2T (UBE2T)

• Hepatocellular carcinoma
• MiR-377-3p
• P53
• THBS1
• Transcription factor EGR1

The oncogene protein ubiquitin-conjugating enzyme E2T (UBE2T) is reported to be upregulated in hepatocellular carcinoma (HCC) and correlated with poor clinical outcomes of HCC patients. However, the underlying mechanism by which UBE2T exerts its oncogenic function in HCC remains largely unexplored. In this study, in vitro and in vivo experiments suggested that UBE2T promoted HCC development including proliferation and metastasis. GSEA analysis indicated that UBE2T was positively correlated with pyrimidine metabolism, and LC/MS-MS metabolomics profiling revealed that the key products of pyrimidine metabolism were significantly increased in UBE2T-overexpressing cells. UBE2T overexpression led to the upregulation of several key enzymes catalyzing de novo pyrimidine synthesis, including CAD, DHODH, and UMPS. Moreover, the utilization of leflunomide, a clinically approved DHODH inhibitor, blocked the effect of UBE2T in promoting HCC progression. Mechanistically, UBE2T increased Akt K63-mediated ubiquitination and Akt/β-catenin signaling pathway activation. The disruption of UBE2T-mediated ubiquitination on Akt, including E2-enzyme-deficient mutation (C86A) of UBE2T and ubiquitination-site-deficient mutation (K8/14 R) of Akt impaired UBE2T’s effect in upregulating CAD, DHODH, and UMPS. Importantly, we demonstrated that UBE2T was positively correlated with p-Akt, β-catenin, CAD, DHODH, and UMPS in HCC tumor tissues. In summary, our study indicates that UBE2T increases pyrimidine metabolism by promoting Akt K63-linked ubiquitination, thus contributing to HCC development. This work provides a novel insight into HCC development and a potential therapeutic strategy for HCC patients.

A number of studies have indicated that Ubiquitin-conjugating enzyme E2T (UBE2T), as an oncogene, promotes progression and metastasis of lung cancer, including lung adenocarcinoma (LUAD), but it is completely unknown whether and how UBE2T is ubiquitylated and degraded, and by which E3 ligase. NEDD4L plays a critical role in the regulation of cellular processes of various cancers, most of which is attributed to its E3 ubiquitin ligase function. However, the relationship between NEDD4L and UBE2T in LUAD has not been elucidated.

The relationship between NEDD4L and UBE2T in LUAD tissues and cells was found by bioinformatic analyses and immunoblotting. Cell counting kit-8, colony formation assay, half-life analysis and the in vivo ubiquitylation assay, generation of xenograft model were performed to determine how NEDD4L regulates UBE2T and its downstream signaling pathway in vitro and in vivo.

Bioinformatic analyses found that NEDD4L, as a potential correlation E3 ligase of UBE2T, was negatively correlated with UBE2T in LUAD. Consistently, UBE2T protein half-life was shortened or extended by NEDD4L overexpression or depletion, respectively. NEDD4L inhibited LUAD cell progression in vitro and in vivo via inducing the ubiquitination-mediated UBE2T degradation, which repressed PI3K-AKT signaling. Similarly, NEDD4L predicted a better patient survival, whereas UBE2T predicted a worse survival.

Collectively, our results reveal that NEDD4L is a novel E3 ligase of UBE2T, which can inhibit PI3K-AKT signaling by targeting for UBE2T ubiquitination and degradation, resulting in repression of LUAD cell progression.

• Lung adenocarcinoma
• NEDD4L
• PI3K-AKT signaling
• UBE2T
• Ubiquitylation

Breast cancer, with high morbidity worldwide, is a threat to the life of women. MiR-543 was identified as playing an active part in the development of breast cancer involving multiple molecules. The goal of this study was to explore the molecular mechanisms of the involvement of miR-543 in the development of breast cancer. Quantitative real-time PCR (qRT-PCR) or Western blotting was used to detect mRNA or protein expression. Cell counting kit-8 (CCK-8), and the 5-bromo-2ʹ-deoxyuridine (BrdU), wound healing, and Transwell assays were the main experimental procedures. Furthermore, subcutaneous tumor formation experiments were conducted to detect the function of miR-543 in breast cancer development in vivo. The match of miR-543 and ubiquitin-conjugating enzyme E2T (UBE2T) was detected through a dual-luciferase reporter experiment and RNA pull-down assay. Based on these results, miR-543 exhibited reduced expression in breast cancer tissues and cell lines, whereas UBE2T exhibited high levels. Furthermore, miR-543 directly targeted UBE2T, and a negative correlation between miR-543 and UBE2T was also observed in breast cancer tissues. Moreover, miR-543 overexpression led to inhibition of viability, proliferation, migration, and invasion of breast cancer. Furthermore, miR-543 overexpression undermined the UBE2T promotional effect by inhibiting ERK/MAPK pathway activity in breast cancer cells. Our study revealed that miR-543 impaired breast cancer progression by targeting UBE2T and downregulating UBE2T expression through the ERK/MAPK pathway, which suggested that miR-543 and UBE2T might serve as promising therapeutic gene targets for breast cancer in clinical application.

• ERK/MAPK pathway
• MCF-7
• MDA-MB-231
• UBE2T
• breast cancer
• miR-543

• cancer
• deubiquitination
• ubiquitin inhibitors
• ubiquitin-proteasome system
• ubiquitination

• Animals
• Antineoplastic Agents/pharmacology
• Humans
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neoplasms/pathology
• Proteasome Endopeptidase Complex/chemistry
• Ubiquitin/metabolism
• Ubiquitin-Protein Ligases/antagonists & inhibitors
• Ubiquitination

• TURSP-2020/ 93 Taif University

Ubiquitin‐conjugating enzyme E2T (UBE2T) has been implicated in many types of cancer including hepatocellular carcinoma (HCC). Epithelial–mesenchymal transition (EMT) process plays a fundamental role during tumor metastasis and progression. However, the molecular mechanisms underlying EMT in HCC in accordance with UBE2T still remain unknown. In this study, we showed that UBE2T overexpression augmented the oncogenic properties and specifically EMT in HCC cell lines, while its silencing attenuated them. UBE2T affected the activation of EMT‐associated signaling pathways: MAPK/ERK, AKT/mTOR, and Wnt/β‐catenin. In addition, we revealed that the epithelial protein complex of E‐cadherin/β‐catenin, a vital regulator of signal transduction in tumor initiation and progression, was totally disrupted at the cell membrane. In particular, we observed that UBE2T overexpression led to E‐cadherin loss accompanied by a simultaneous elevation of both cytoplasmic and nuclear β‐catenin, while its silencing resulted in a strong E‐cadherin turnover at the cell membrane. Interestingly, chemical inhibition of the MAPK/ERK, AKT/mTOR, and Wnt/β‐catenin signaling pathways demonstrated that the nuclear translocation of β‐catenin and subsequent EMT was enhanced mainly by MAPK/ERK. Collectively, our findings demonstrate the UBE2T/MAPK‐ERK/β‐catenin axis as a critical regulator of cell state transition and EMT in HCC.

• E-cadherin
• EMT
• HCC
• MAPK/ERK
• UBE2T
• β-catenin

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Via analysis using The Cancer Genome Atlas database, the present study identified 1,835 genes that were differentially expressed in CRC, including 811 upregulated and 1,024 downregulated genes. Enrichment analyses using the Database for Annotation, Visualization and Integrated Discovery tool revealed that these differentially expressed genes were associated with the regulation of CRC progression by modulating multiple pathways, such as ‘Cell Cycle, Mitotic’, ‘DNA Replication’, ‘Mitotic M-M/G1 phases’ and ‘ATM pathway’. To identify the key genes in CRC, protein-protein interaction (PPI) network analysis was performed and the hub modules in upregulated and downregulated PPI networks were identified. Ubiquitin-conjugating enzyme E2 T (UBE2T), a member of the E2 family, was identified to be a key regulator in CRC. To the best of our knowledge, the present study was the first to demonstrate that UBE2T expression was upregulated in CRC samples compared with normal tissues. Kaplan-Meier analysis revealed that higher expression levels of UBE2T were associated with worse prognosis compared with lower UBE2T expression levels in CRC. Additionally, the present study demonstrated that knockdown of UBE2T inhibited CRC cell proliferation. Flow cytometry assays revealed that UBE2T knockdown induced cell cycle arrest at G₁ phase and apoptosis in vitro. These results suggested that UBE2T may be a novel potential biomarker for CRC.

• colorectal cancer
• differentially expressed genes
• prognosis
• proliferation
• ubiquitin-conjugating enzyme E2 T

Ubiquitin-conjugating enzyme E2T (UBE2T) acts as an oncogene in various types of cancer. However, the mechanisms behind its oncogenic role remain unclear in lung cancer. This study aims to explore the function and clinical relevance of UBE2T in lung cancer.

Lentiviral vectors were used to mediate UBE2T depletion or overexpress UBE2T in lung cancer cells. CCK8 analysis and western blotting were performed to investigate the effects of UBE2T on proliferation, autophagy, and relevant signaling pathways. To exploit the clinical significance of UBE2T, we performed immunohistochemistry staining with an anti-UBE2T antibody on 131 NSCLC samples. Moreover, we downloaded the human lung adenocarcinoma (LUAD) dataset from The Cancer Atlas Project (TCGA). Lasso Cox regression model was adopted to establish a prognostic model with UBE2T-correlated autophagy genes.

We found that UBE2T stimulated proliferation and autophagy, and silencing this gene abolished autophagy in lung cancer cells. As suggested by Gene set enrichment analysis, we observed that UBE2T downregulated p53 levels in A549 cells and vice versa. Blockade of p53 counteracted the inhibitory effects of UBE2T depletion on autophagy. Meanwhile, the AMPK/mTOR signaling pathway was activated during UBE2T-mediated autophagy, suggesting that UBE2T promotes autophagy via the p53/AMPK/mTOR pathway. Interestingly, UBE2T overexpression increased cisplatin-trigged autophagy and led to cisplatin resistance of A549 cells, whereas inhibiting autophagy reversed drug resistance. However, no association was observed between UEB2T and overall survival in a population of 131 resectable NSCLC patients. Therefore, we developed and validated a multiple gene signature by considering UBE2T and its relevance in autophagy in lung cancer. The risk score derived from the prognostic signature significantly stratified LUAD patients into low- and high-risk groups with different overall survival. The risk score might independently predict prognosis. Interestingly, nomogram and decision curve analysis demonstrated that the signature’s prognostic accuracy culminated while combined with clinical features. Finally, the risk score showed great potential in predicting clinical chemosensitivity.

We found that UBE2T upregulates autophagy in NSCLC cells by activating the p53/AMPK/mTOR signaling pathway. The clinical predicting ability of UBE2T in LUAD can be improved by considering the autophagy-regulatory role of UBE2T.

The online version contains supplementary material available at 10.1186/s12967-021-03056-1.

• Autophagy
• Lung cancer
• Prognostic signature
• UBE2T
• p53

• RNAi
• Thermal stress
• Turbot Scophthalmus maximus
• UPP
• p53
• ube2h

• DUSP12
• Hepatocellular carcinoma
• Mutation
• Prognosis
• Tumorigenesis

• UBE2T
• beta-catenin
• cancer stem cells
• hepatocellular carcinoma

The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 (conjugating)‒E3 (ligating) enzyme cascade. Thus, E2 enzymes act as the central players in the ubiquitination system, modulating various pathophysiological processes in the tumor microenvironment. In this review, we summarize the types and functions of E2s in various types of cancer and discuss the possibility of E2s as targets of anticancer therapeutic strategies.

• cancer
• ubiquitin-conjugating enzyme
• ubiquitination

MicroRNAs (miRNAs) function as important regulators of gene expression involved in tumor pathogenesis, including retinoblastoma. However, the expression profiles and potential roles in retinoblastoma are still largely unclear.

Differentially expressed miRNAs (DEmiRs) and genes (DEGs) in retinoblastoma were extracted from Gene Expression Omnibus (GEO) repository. Expression levels of miR-340 and WIF1 were detected in retinoblastoma tissues and cell lines by qRT-PCR. Both gain-of-function and loss-of-function experiments were performed to explore the effects of miR-340 on cell proliferation, migration and invasion. Bioinformatics analysis and luciferase reporter assay were used to explore the interaction between miR-340 and WIF1.

A total of 11 DEmiRs were identified in retinoblastoma tissue and blood samples. Among them, we validated that miR-340 was the most highly expressed miRNA and correlated with tumor size, ICRB stage and optic nerve invasion. miR-340 was observed to enhance the proliferation, migration and invasion capacity of retinoblastoma cells. We then identified 26 DEGs from 3 retinoblastoma GEO datasets and subsequently constructed a miRNA–mRNA regulatory network. Further analysis revealed that WIF1 was a direct target of miR-340. Moreover, overexpression of WIF1 could repress retinoblastoma progression induced by miR-340 in vitro and in vivo.

Collectively, miR-340 functioned as an oncomiRNA to promote retinoblastoma cell proliferation, migration and invasion via regulating WIF1. Our data also provided multiple miRNAs and genes that may contribute to a better understanding of retinoblastoma pathogenesis.

• WIF1
• invasion
• miR-340
• proliferation
• retinoblastoma

Reportedly, ubiquitin-conjugating enzyme E2T (UBE2T) is closely related to the progression of several malignancies. This work is aimed to probe the role of UBE2T in the progression of hepatocellular carcinoma (HCC) patients. The microarray analysis was executed to screen the differentially expressed genes (DEGs) in HCC tissues. The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases, PCR and immunohistochemistry were utilized to validate the dysregulation of UBE2T in HCC. Kaplan-Meier analysis was employed to determine the relationship between UBE2T expression and the prognosis of HCC patients. PCR was carried out to detect UBE2T protein expression in HCC cell lines. Cell Counting Kit-8 (CCK-8) assay and 5-bromo-2ʹ-deoxyuridine (BrdU) experiments were conducted to examine the proliferation of HCC cells. Scratch healing and Transwell experiments were conducted to examine the migration of HCC cells. Bioinformatics analysis and dual-luciferase reporter gene experiments predicted and validated the targeting relationship with miR-212-5p and UBE2T. We found that UBE2T expression was remarkably up-modulated in HCC tissues and cell lines, and its high expression was linked to a worse prognosis in HCC patients. UBE2T overexpression enhanced HCC cell proliferation and migration. Additionally, UBE2T was verified as a downstream target of miR-212-5p. In conclusion, UBE2T overexpression is markedly linked to unfavorable prognosis in HCC patients. UBE2T, regulated by miR-212-5p, significantly enhances the malignant phenotypes of HCC cells, which can be used as a target for HCC diagnosis and prognosis.

• HCC
• UBE2T
• miR-212-5p
• migration

• chronic hepatitis B virus infection
• hepatocellular carcinoma
• molecular processes
• protein-protein interactions
• signaling pathways

Background: The ubiquitin-conjugating enzyme E2 T (UBE2T) has been shown to contribute to several types of cancer. However, no publication has reported its implication in esophageal squamous cell cancer (ESCC).

Methods: We explored several public databases, including The Cancer Genome Atlas (TCGA), Oncomine, and gene expression Omnibus (GEO). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA) were adopted to explore involved signaling pathways. We used R software to develop prognostic gene signatures with the LASSO and stepwise Cox regression analysis, separately. Immunohistochemistry staining was performed to detect UBE2T in 90 ESCC patients, followed by survival analysis. We also used an R package pRRophetic to evaluate chemotherapy sensitivity for the TCGA–ESCC cohort.

Results: We found significantly increased UBE2T transcript levels and DNA copy numbers in ESCC tissues. UBE2T was associated with the p53 signaling pathway, cell cycle, Fanconi anemia pathway, and DNA replication, as indicated by Go, KEGG pathway enrichment analysis. These pathways were also upregulated in ESCC. The prognostic signatures with UBE2T-associated genes could stratify ESCC patients into low- and high-risk groups with significantly different overall survival in the TCGA–ESCC cohort. We also validated the association of UBE2T with unfavorable survival in 90 ESCC patients recruited for this study. Moreover, we found that the low-risk group was significantly more sensitive to chemotherapy than the high-risk group.

Conclusions: UBE2T is involved in the development of ESCC, and gene signatures derived from UBE2T-associated genes are predictive of prognosis in ESCC.

• ESCC
• TCGA
• UBE2T
• immunohistochemistry
• prognosis

Ubiquitin-conjugating enzymes (E2s) are one of the three enzymes required by the ubiquitin-proteasome pathway to connect activated ubiquitin to target proteins via ubiquitin ligases. E2s determine the connection type of the ubiquitin chains, and different types of ubiquitin chains regulate the stability and activity of substrate proteins. Thus, E2s participate in the regulation of a variety of biological processes. In recent years, the importance of E2s in human health and diseases has been particularly emphasized. Studies have shown that E2s are dysregulated in variety of cancers, thus it might be a potential therapeutic target. However, the molecular basis of E2s as a therapeutic target has not been described systematically. We reviewed this issue from the perspective of the special position and role of E2s in the ubiquitin-proteasome pathway, the structure of E2s and biological processes they are involved in. In addition, the inhibitors and microRNAs targeting E2s are also summarized. This article not only provides a direction for the development of effective drugs but also lays a foundation for further study on this enzyme in the future.

• E2s
• NF-κB
• cancer
• inhibitors
• target
• ubiquitin-conjugating enzymes

• Animals
• Apoptosis
• Cell Cycle
• DNA Repair
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• MicroRNAs/metabolism
• NF-kappa B/metabolism
• Neoplasms/metabolism
• Neoplasms/therapy
• Protein Conformation
• Signal Transduction
• Substrate Specificity
• Ubiquitin-Conjugating Enzymes/chemistry
• Ubiquitin-Protein Ligases/metabolism

• CRC
• E-cadherin
• UBE2T
• Ubiquitination
• p53

• PSMC2
• carcinogenesis
• cell proliferation
• hepatocellular carcinoma
• p21

Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade β-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated β-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/β-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.

• Breast cancer (BCa)
• PI3K/AKT
• glycolysis
• invasion
• proliferation
• ubiquitin-coupled enzyme E2T (UBE2T)

• UBE2T
• UBE2s
• bioinformatics analysis
• immunohistochemistry
• ovarian cancer
• prognostic value

Radioresistance is the major obstacle in radiation therapy (RT) for hepatocellular carcinoma (HCC). Dysregulation of DNA damage response (DDR), which includes DNA repair and cell cycle checkpoints activation, leads to radioresistance and limits radiotherapy efficacy in HCC patients. However, the underlying mechanism have not been clearly understood.

We obtained 7 pairs of HCC tissues and corresponding non-tumor tissues, and UBE2T was identified as one of the most upregulated genes. The radioresistant role of UBE2T was examined by colony formation assays in vitro and xenograft tumor models in vivo. Comet assay, cell cycle flow cytometry and γH2AX foci measurement were used to investigate the mechanism by which UBE2T mediating DDR. Chromatin fractionation and immunofluorescence staining were used to assess cell cycle checkpoint kinase 1(CHK1) activation. Finally, we analyzed clinical data from HCC patients to verify the function of UBE2T.

Here, we found that ubiquitin-conjugating enzyme E2T (UBE2T) was upregulated in HCC tissues, and the HCC patients with higher UBE2T levels exhibited poorer outcomes. Functional studies indicated that UBE2T increased HCC radioresistance in vitro and in vivo. Mechanistically, UBE2T-RNF8, was identified as the E2-E3 pair, physically bonded with and monoubiquitinated histone variant H2AX/γH2AX upon radiation exposure. UBE2T-regulated H2AX/γH2AX monoubiquitination facilitated phosphorylation of CHK1 for activation and CHK1 release from the chromatin to cytosol for degradation. The interruption of UBE2T-mediated monoubiquitination on H2AX/γH2AX, including E2-enzyme-deficient mutation (C86A) of UBE2T and monoubiquitination-site-deficient mutation (K119/120R) of H2AX, cannot effectively activate CHK1. Moreover, genetical and pharmacological inhibition of CHK1 impaired the radioresistant role of UBE2T in HCC. Furthermore, clinical data suggested that the HCC patients with higher UBE2T levels exhibited worse response to radiotherapy.

Our results revealed a novel role of UBE2T-mediated H2AX/γH2AX monoubiquitination on facilitating cell cycle arrest activation to provide sufficient time for radiation-induced DNA repair, thus conferring HCC radioresistance. This study indicated that disrupting UBE2T-H2AX-CHK1 pathway maybe a promising potential strategy to overcome HCC radioresistance.

Supplementary information accompanies this paper at 10.1186/s13046-020-01734-4.

• Cell cycle arrest
• H2AX monoubiquitination
• Hepatocellular carcinoma
• Radioresistance
• Ubiquitin-conjugating enzyme E2T