Jul 2026· Frontiers in Cell and Developmental Biology· Vol 14· 0 citations· 118 references
Medicine
TL;DR
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.
Abstract
BRCA1-associated protein 1 (BAP1) is a deubiquitinase (DUB) localized in both the nucleus and cytoplasm and is widely recognized as a tumor suppressor. Germline and somatic alterations in BAP1 have been strongly associated with increased susceptibility to diverse cancer types and with adverse clinical outcomes. Although BAP1 is best known for its role in epigenetic regulation, particularly through the modulation of histone H2A monoubiquitination (H2Aub) and gene transcription, accumulating evidence suggests that its functional repertoire extends well beyond these canonical activities. BAP1 is increasingly viewed as a central molecular hub through which fundamental cellular processes are integrated and coordinated via its catalytic activity and dynamic protein interaction networks. In this review, the pleiotropic functions of BAP1 are systematically examined across several biological dimensions, including epigenetic regulation, genomic stability, cellular metabolism, and cell fate determination. Notably, BAP1-mediated regulation is highly context dependent, as cell type, differentiation status and tumor microenvironmental (TME) cues may shape its downstream effects and contribute to heterogeneous biological outcomes. By synthesizing these multidimensional regulatory mechanisms, this review provides an integrated overview of the molecular features and functional roles of BAP1, with particular emphasis on its impacts on the regulation of cell death including apoptosis, ferroptosis and disulfidptosis. Collectively, these insights underscore the evolving understanding of BAP1 biology over the past decade and highlight the need for renewed attention to this critical tumor suppressor and its therapeutic potential in cancer.
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
Breast cancer continues to present formidable clinical challenges, particularly in triple-negative and endocrine-resistant subtypes where adaptive stress mechanisms drive therapeutic failure. Nuclear protein 1 (NUPR1), an intrinsically disordered protein, has emerged as a non-mutational hub that has been implicated in integrating metabolic, transcriptional, and cell-survival signals associated with malignant progression. This Review examines how NUPR1 transduces mitogenic stimuli into anabolic programs, while orchestrating autophagic flux, lysosomal biogenesis, and ferroptosis evasion to maintain cellular fitness under oncogenic and therapeutic stress. We discuss its causal roles in endocrine and chemoresistance through chromatin-associated cooperation with estrogen receptor α, activation of DNA-damage repair, and cell-cycle checkpoint control, as well as its contributions to metastatic dissemination via extracellular vesicle-mediated niche remodeling and immunosuppressive macrophage polarization. Furthermore, we evaluate emerging therapeutic avenues, from small-molecule inhibitors and single-domain antibody degraders that disrupt NUPR1 nuclear trafficking, to metabolic drug repurposing strategies such as statins that intercept the insulin–NUPR1 axis. Elucidating NUPR1 biology represents a paradigm shift toward targeting dynamic, stress-adaptive dependencies in breast cancer, offering new precision-oncology opportunities.
Bo Xiang, Tao Liu, Duo Xu et al.· Frontiers in Physiology· 0 citations
Mesothelioma is a highly aggressive malignancy that develops through the combined influence of several factors, including environmental exposure, genetic susceptibility, immune status, and aberrant activation or dysregulation of signaling pathways. The BAP1 gene, a tumor suppressor located at chromosome 3p21.1, plays a pivotal role in maintaining genomic stability by functioning as a deubiquitinating enzyme in critical processes such as DNA damage repair, cell cycle regulation, and chromatin remodeling. Its proper activity requires nuclear localization via the nuclear localization signal (NLS) domain. When BAP1 undergoes a truncation mutation, the NLS loses its function and the protein is retained in the cytoplasm; whereas missense mutations in the UCH domain, whilst not necessarily altering subcellular localisation, can directly lead to the loss of deubiquitinase activity, thereby promoting tumour development.Consequently, elucidating the signaling pathways governed by BAP1, designing targeted therapeutic strategies for BAP1-mutant cancers, and implementing preventive interventions in BAP1 mutation carriers represent urgent clinical and research priorities.
Wan-Ting Xuan, Yao Dong, Sitong Ma et al.· Clinical and Experimental Me...· 0 citations
This work provides a comprehensive framework that clarifies recent controversies—such as whether H4K16ac primarily governs transcription or replication timing, and which KAT8-containing complex catalyzes, which acetylation mark—and establishes a rationale for future precision-targeting strategies and biomarker development grounded in KAT8 functional heterogeneity.
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.
