Aug 2026· Drug Design, Development and Therapy· Vol 20· 0 citations· 213 references
Medicine
TL;DR
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.
Abstract
Abstract The ubiquitin-proteasome system (UPS) plays a central role in regulating protein homeostasis and degradation. Its dysregulation is closely associated with various diseases, including cancer. S-phase kinase-associated protein 2 (SKP2) is a key E3 ubiquitin ligase component of the UPS. It induces proteasome-mediated protein degradation or modulates substrate function by conjugating K48-linked or K63-linked ubiquitin chains to diverse target proteins. Recent studies have shown that the overexpression of SKP2 in several cancer types is correlated with poor clinical outcomes, underscoring its potential as a therapeutic target. Notably, emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment (TME) and immunotherapy response, positioning it as an increasingly attractive target for intervention. In this review, the oncogenic properties of SKP2 and its underlying mechanisms were elucidated in multiple cancer types. Moreover, we systematically summarized future directions for SKP2-targeted therapy.
Ubiquitin-specific protease 28 (USP28) is a deubiquitinating enzyme initially identified as a regulator that stabilizes p53 and c-MYC in response to DNA damage stress. Beyond its role in maintaining genomic integrity and cell cycle checkpoints, USP28 is implicated in diverse pathological processes. In various solid tumors, including lung, pancreatic, ovarian, and hepatocellular carcinomas, USP28 is markedly upregulated; it promotes proliferation, metabolic reprogramming, invasion, and therapeutic resistance by stabilizing oncoproteins such as c-Myc, STAT3, and SOX9. Conversely, in specific contexts like breast cancer and certain melanomas, USP28 deficiency drives malignant progression, revealing a context-dependent functional duality. These findings underscore the complexity of USP28 signaling and highlight its potential as a therapeutic target for precision medicine. This review summarizes 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.
Tongyong Luo, Shuncai Wu, Qingsong Wang et al.· Frontiers in Immunology· 0 citations
Preclinical evidence suggests that KIF23 is a molecule with significant translational potential, demonstrating promising prospects in disease diagnosis, prognostic assessment, and targeted therapy, and further in-depth research on KIF23 will significantly advance precision medicine.
Yi Liu, Yu Luo, Pinghong Hu et al.· Cancer Cell International· 0 citations
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.
ABSTRACT F‐box protein 11 (FBXO11), a critical component of the F‐box protein family, serves as the substrate recognition subunit of the Skp1‐Cul1‐F‐box (SCF) E3 ubiquitin ligase complex, orchestrates the ubiquitination and proteasomal degradation of a diverse array of substrates, thereby regulating various physiological and pathological processes. Emerging evidence reveals that FBXO11 is aberrantly expressed in multiple tumor types. Predominantly, FBXO11 functions as a potent tumor suppressor, and its downregulation is strongly correlated with tumor initiation, aggressive progression, and poor prognoses. Mechanistically, FBXO11 deficiency facilitates tumor development and metastasis by deregulating the cell cycle progression, enhancing cell migration and invasion, and driving epithelial‐mesenchymal transition (EMT). However, the broad substrate spectrum of FBXO11 dictates its context‐dependent roles in cancer biology, imparting significant challenges to its direct therapeutic targeting, as systemic modulation may yield unpredictable off‐target or paradoxical effects. This review provides a comprehensive overview of current understanding of FBXO11 in oncology. By critically appraising its substrate diversity and functional versatility, we aim to re‐evaluate the clinical translation of FBXO11, proposing that it be regarded not merely as a straightforward therapeutic target, but rather as a prognostic biomarker and a context‐specific vulnerability that necessitates precision medicine strategies for effective clinical intervention.
Yuqi Zhang, Changyi Fan, Shiheng Chen et al.· Cancer Science· 0 citations
An integrated overview of the molecular features and functional roles of BAP1 is provided, with particular emphasis on its impacts on the regulation of cell death including apoptosis, ferroptosis and disulfidptosis.
Kexin Fan, Jun Yao, Shaobo Wu et al.· Frontiers in Cell and Develo...· 0 citations
Ubiquitin-specific protease 2 (USP2), a pivotal member of the deubiquitinating enzyme family, has emerged as a critical but context-dependent regulator in cancer, exhibiting paradoxical tumor-suppressive and oncogenic functions. This duality is governed by its ability to stabilize specific substrate proteins, thereby modulating central signaling hubs including the p53, Wnt/β-catenin, PI3K/Akt, and cell cycle networks. Through these axes, USP2 profoundly influences hallmark cancer phenotypes such as sustained proliferation, metabolic reprogramming, metastatic progression, immune evasion, and therapy resistance. This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword. We detail how specific interactions between USP2 and its substrates dictate its pro-tumorigenic or anti-tumorigenic outcomes, depending on the tissue and microenvironment. Furthermore, we comprehensively evaluate the landscape of emerging USP2 inhibitors, discussing their therapeutic potential and the significant challenges posed by USP2's functional duality, substrate promiscuity, and isoform diversity. Targeting USP2 presents a promising yet intricate avenue for cancer therapy, necessitating future research focused on patient stratification, combination strategies, and the development of context-specific inhibitors.
Peng Hao, Jiale Wan, Zhangyu Guo et al.· Biochimica et biophysica act...· 0 citations
