This review explores the mechanistic involvement of UBE2C in diverse cancers, with a particular focus on its involvement in DNA damage repair mediated by the anaphase-promoting complex (APC/C).
Abstract
The ubiquitin-proteasome system (UPS) is an important regulator of numerous cellular pathways, including DNA repair, protein degradation, the cell cycle, and signal transduction. UBE2C, a member of the ubiquitin-conjugating enzyme family, facilitates the ubiquitination of essential cellular regulators. Notably, UBE2C is consistently overexpressed in breast, lung, brain, hepatocellular, and ovarian carcinomas. Increased UBE2C expression is associated with tumour aggressiveness, genomic instability, epithelial-to-mesenchymal transition, and resistance to chemotherapy and radiotherapy. Our review explores the mechanistic involvement of UBE2C in diverse cancers, with a particular focus on its involvement in DNA damage repair mediated by the anaphase-promoting complex (APC/C). Furthermore, the regulatory effects of miR-381, miR-503, and miR-205 on UBE2C expression were examined, highlighting the promising prospects of these miRNAs for targeted cancer therapy. The involvement of UBE2C in different cancer hallmarks underscores its potential as a biomarker and therapeutic target. A comprehensive understanding of its mechanistic involvement in cell cycle regulation and DNA repair will further enhance its application in diagnostics, personalised medicine, and precision medicine.
A review of the molecular characteristics and physiological functions of USP28, its context-dependent roles in neoplastic diseases, and its translational implications for targeted therapy and biomarker discovery highlights its potential as a therapeutic target for precision medicine.
Tongyong Luo, Shuncai Wu, Qing-Song Wang et al.· Frontiers in Immunology· 1 citation
Emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment and immunotherapy response, positioning it as an increasingly attractive target for intervention.
Sheng-An Zheng, Cheng Wang, Xiao-Die Yao et al.· Drug Design, Development and...· 0 citations
Objective: The ubiquitin system plays a central role in regulating intracellular protein homeostasis and cellular signaling. E3 ubiquitin ligases, in particular, are key modulators of protein degradation and have been implicated in cancer progression, including breast cancer. DHRS2, a gene known to suppress MDM2 activity through its ubiquitin-binding domain, has recently emerged as a potential regulator in tumor biology. This study investigated how DHRS2 expression influences selected E3 ubiquitin ligase genes in breast epithelial cells.Materials and Methods: MCF-7 and MCF-10A cell lines were used. DHRS2 was either overexpressed using a vector-based system, or silenced via siRNA. After transfection, quantitative reverse transcription polymerase chain reaction (qRT–PCR) was performed to evaluate changes in the expression levels of BRCA1, BARD1, and STUB1.Results: In MCF-7 cells, DHRS2 overexpression induced a fourfold increase in BRCA1 expression, whereas STUB1 and BARD1 were downregulated (0.56-fold). In MCF-10A cells with naturally low DHRS2, STUB1 expression increased 1.5-fold after DHRS2 knockdown, and BARD1 expression correlated positively with DHRS2 levels.Conclusion: This study highlights a potential regulatory link between DHRS2 and key E3 ubiquitin ligases-BRCA1, BARD1, and STUB1. Differential patterns across cell types indicate DHRS2 as a context-dependent modulator of ubiquitin-mediated pathways, supporting its relevance in biomarker discovery and therapeutic targeting in breast cancer.
Chemotherapy remains central to breast cancer treatment, particularly for aggressive subtypes like triple-negative breast cancer. Despite its widespread use, the toxicity of chemotherapeutic agents and frequent resistance limit clinical success. Epigenetic therapy offers a promising translational approach due to its reversible modulation of gene expression via histone and non-histone modifications that regulate key signaling pathways, including those involved in DNA repair. CREB-binding protein (CBP), a key histone acetyltransferase, is involved in ATM activation, a central component of the DNA damage response. The loss of CBP was found to sensitize breast cancer cells to chemo- and radiotherapy, thereby identifying CBP as a potential therapeutic vulnerability. In the present study, we investigated the proteomic consequences of pharmacological inhibition of CBP in breast cancer cells using two domain-specific inhibitors, C646 (HAT domain) and inobrodib (bromodomain), and assessed their translational potential in combination with doxorubicin. Using in vitro and in vivo breast cancer models, we showed that CBP inhibition disrupts DNA repair and cell-cycle regulatory pathways, thereby enhancing doxorubicin-induced cytotoxicity and apoptosis. Interestingly, the combination groups displayed the most pronounced effects on tumor growth and showed elevated levels of cleaved caspase-3, while suppression of ki67 expression and H3K27 acetylation. Additionally, the combination of CBP inhibitors with doxorubicin did not affect the body weight or the organ indices. These findings support a rational epigenetic-chemotherapy combination approach and provide preliminary preclinical evidence for further investigation of CBP-targeted strategies to improve chemotherapy efficacy while mitigating toxicity.
Wafaa S. Ramadan, Iman M. Talaat, A. Al-Azawi et al.· Translational Research: The...· 0 citations
The molecular mechanisms by which the UPS contributes to targeted therapy resistance in NSCLC are summarized, recent progress in emerging UPS-targeting strategies are evaluated, and the major barriers impeding their clinical translation are critically discussed.
BACKGROUND
RING finger protein 126 (RNF126) is an E3 ubiquitin ligase that is overexpressed in various malignancies. However, its role in ovarian cancer remains poorly understood.
METHODS
Ovarian cancer cell lines, including SKOV3, A2780, and cisplatin-resistant SKOV3/DDP, were utilized in this study. RNF126 expression was modulated via lentiviral transduction. Cell viability, colony formation, and migration were assessed by cell counting kit-8 (CCK-8), colony formation, and Transwell assays. Protein and mRNA levels were measured by Western blotting and real-time quantitative PCR (qPCR). Protein interaction was evaluated by co-immunoprecipitation and ubiquitination assays. In vivo tumor growth and cisplatin response were examined using a xenograft model.
RESULTS
In SKOV3 and A2780 cells, RNF126 overexpression promoted proliferation, colony formation, and migration, while its knockdown produced the opposite effects. Notably, elevated RNF126 expression was observed in the cisplatin-resistant SKOV3/DDP line. Silencing RNF126 in these cells increased cisplatin sensitivity while concurrently reducing proliferative capacity, clonogenicity, and migratory potential. RNF126 depletion in SKOV3/DDP cells led to decreased mRNA and protein expression of Notch1 and its downstream targets Myc, Cyclin D3, and Hes1. Meanwhile, Numb mRNA levels remained unchanged, whereas its protein levels increased, indicating post-transcriptional regulation. Furthermore, Numb silencing increased cell viability, clonality, migration, and Notch signaling activation in RNF126 knockdown SKOV3/DDP cells. In vivo, silencing RNF126 markedly enhanced the sensitivity of cells to cisplatin, suppressed tumor growth, and inhibited Myc, Cyclin D3, Hes1, and Notch1 protein expression. Silencing Numb can reverse the inhibitory effects of RNF126 knockdown. Mechanistic studies showed that RNF126 directly binds to the Notch signaling inhibitor Numb and mediates its ubiquitination and proteasomal degradation, thereby activating the Notch1 signaling pathway and upregulating its downstream genes. In addition, analysis of the TCGA dataset revealed that elevated RNF126 expression is a significant prognostic factor associated with increased mortality risk in ovarian cancer.
CONCLUSIONS
These findings establish RNF126 as a critical contributor to cisplatin resistance in ovarian cancer via regulation of the Numb/Notch1 pathway and highlight its potential as a therapeutic target to counteract chemoresistance.
Tian-Jiao Zheng, Han Wu, Li Niu et al.· Frontiers in Bioscience· 0 citations
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