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.
Abstract
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.
This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword, and comprehensively evaluates the landscape of emerging USP2 inhibitors.
Peng Hao, Jiale Wan, Zhangyu Guo et al.· Biochimica et biophysica act...· 0 citations
Ubiquitin-specific protease 48 (USP48) is a deubiquitinase (DUB) belonging to the USP subfamily, the largest and functionally most diverse class of DUBs. As a critical post-translational regulator, USP48 governs a wide range of physiological and pathological processes, with well-established and context-dependent roles in tumorigenesis, cancer progression, and therapeutic resistance. Mechanistically, USP48 displays remarkable specificity for distinct lysine-linked ubiquitin chains on substrate proteins, thereby preventing their proteasomal degradation and precisely modulating their subcellular localization and enzymatic activity. This regulatory function orchestrates core cellular programs including the DNA damage response, cell cycle checkpoint control, and tumor immune microenvironment remodeling, through modulation of the MDM2/p53, PI3K/Akt, and NF-κB signaling axes via both catalytic and non-catalytic mechanisms. A defining feature of USP48 is its striking context-dependent functional duality: while it predominantly functions as an oncogenic driver, it exerts tumor suppressor activity in specific tissue and genetic contexts. Emerging studies have further expanded its pathophysiological spectrum to include sorafenib resistance in hepatocellular carcinoma, sepsis-associated acute lung injury, and diabetic microvascular complications. In this review, we systematically synthesize current advances in USP48 structure, substrate specificity, molecular mechanisms, and disease-specific functions, provide a critical evaluation of preclinical USP48-targeted therapeutic strategies, and delineate the major conceptual and translational challenges impeding the clinical development of USP48-based interventions.
Hu Lei, Chujiao Zhu, Li Yang et al.· Biochemical and Biophysical...· 0 citations
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
DExH-box helicase 9 (DHX9) is a multifunctional nucleic acid helicase that participates in R-loop homeostasis, genome maintenance, RNA metabolism, and innate immune signaling. Accumulating evidence has linked aberrant DHX9 expression or activity to tumorigenesis, tumor progression, treatment response, and patient prognosis. However, its role in cancer is highly context-dependent, rather than uniformly oncogenic or tumor suppressive. Depending on its molecular partners, subcellular localization, post-translational modifications, tumor genotype, and immune microenvironment, DHX9 may either promote malignant phenotypes or contribute to tumor-restraining processes. In this review, we summarize the molecular characteristics and regulatory properties of DHX9, discuss its roles in genome stability, transcriptional and post-transcriptional control, circular RNA (circRNA) biogenesis, and tumor-immune crosstalk, and evaluate its emerging value as a potential biomarker and therapeutic target. We also highlight key challenges in this field, including mechanistic heterogeneity, insufficient translational validation, and the urgent need for context-informed patient stratification to maximize the clinical utility of DHX9-targeted strategies.
Yejin Cai, Ziyuan Chen, Jiaying Xiong et al.· Biochimica et biophysica act...· 0 citations
Esophageal squamous cell carcinoma (ESCC) is a significantly fatal gastrointestinal malignancy worldwide, with complex proteomic remodeling during its onset and progression. Despite advancements in existing multimodal therapy regimens, the prognosis for advanced patients remains inadequate, necessitating the urgent identification of novel therapeutic targets. The Ubiquitin-proteasome system is the principal regulatory mechanism for intracellular protein homeostasis, with deubiquitinating enzymes (DUBs) serving as crucial 'editors' that reverse ubiquitination modifications, significantly influencing the stability, localization and functional regulation of oncoproteins. This review aims to systematically delineate the complex regulatory network of DUBs in ESCC, comprehensively investigate their specific mechanisms within critical oncogenic signaling pathways, including TGF-β, Wnt/β-catenin, NF-κB and Hippo, as well as their roles in epithelial-mesenchymal transition, epigenetic remodeling and the regulation of the immune microenvironment. Furthermore, this review provides a novel cross-cancer perspective by comparing the similarities and differences of DUBs in ESCC and uterine corpus endometrial carcinoma to determine the conserved and tissue-specific functions of ubiquitin-specific protease (USP)14, USP7 and BRCA1-associated protein 1. Furthermore, the preclinical research progress of small molecule inhibitors and proteolysis-targeting chimeras targeting DUBs was also assessed to identify the theoretical basis and translational pathway for the development of next-generation precision oncology therapies.
Yu Zhao, Chenghai He, Kexin Chen et al.· International Journal of Onc...· 1 citation
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).
