Aug 2026· Cell Reports· pp.
117649
· 0 citations· 99 references
Medicine
TL;DR
A small molecule inhibitor is repurposed to interfere with its binding to DNA, restrict chromatin accessibility at promoters, and constrain tumor growth both in vitro and in vivo to show how increased HMGB2 availability represents a transcriptional addiction that fuels cell-cycle progression and growth.
Abstract
Pancreatic cancer remains at a stagnant 5-year survival of <13%, attributed to the high heterogeneity and plasticity of these tumors. To circumvent this, we focus on the abundant nuclear protein high mobility group-box protein 2 (HMGB2). HMGB2 depletion is key for establishing replicative senescence in normal cells, but it is significantly overexpressed across multiple cancer types. Here, we combine single-cell and spatial genomics with patient-derived organoids and tumor samples to show how increased HMGB2 availability represents a transcriptional addiction that fuels cell-cycle progression and growth. We repurpose a small molecule inhibitor targeting HMGB2 to interfere with its binding to DNA, restrict chromatin accessibility at promoters, and constrain tumor growth both in vitro and in vivo. 3D chromatin interactions involving HMGB2-bound enhancers and promoters also collapse upon drug treatment. Thus, pharmacological HMGB2 targeting represents a universal strategy for managing cancer progression irrespective of its genetic or molecular characteristics.
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
Esophageal squamous cell carcinoma (ESCC) is a highly prevalent malignancy worldwide. Moreover, ESCC remains poorly characterized at the molecular level, which contributes to limited therapeutic options and an overall poor prognosis. In this context, HMGA family members, which are overexpressed in tumors but almost absent in healthy adult tissues, seem to represent promising therapeutic targets. These proteins act by binding to AT-hook DNA-binding motifs and may regulate the expression of several genes associated with tumor progression. Therefore, integrating in silico, translational, and in vitro approaches, we investigated the functional consequences of blocking HMGA2–DNA interaction in ESCC tumor progression by using netropsin, a site-specific ligand for AT-rich DNA regions. Our results demonstrate that netropsin treatment significantly reduced cell viability, migration, and cell cycle progression, thereby promoting apoptosis. Furthermore, netropsin treatment was capable of partially reverting Epithelial–Mesenchymal Transition (EMT) activation associated with HMGA2 expression, by downregulating EMT activators, such as Slug and Twist. Finally, the netropsin treatment sensitizes ESCC cells to chemotherapeutic treatment with 5-Fluorouracil. Taken together, our findings highlight that AT binding-specific blockade could be correlated with the inhibition of HMGA2 and may reveal a promising approach to better understand ESCC progression.
Lucas de Jesus Lima, Matheus Lohan-Codeço, Maria Luísa Barambo Wagner et al.· International Journal of Mol...· 0 citations
Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity and impaired differentiation during tissue development. Normal development requires precise patterns of gene expression programs, which are regulated by epigenetic-modifying complexes. Epigenetic regulation of transcription is critical for maintaining a de-differentiated oncogenic state in cancers, particularly pediatric, and targeting disease-relevant epigenetic regulators can exhibit antitumor activity.
To identify protein complex-level dependencies required for neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), is a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits (i.e. PCGF1, BCOR, and KDM2B) reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of non-canonical PRC1.1 exist, co-dependency analysis of PRC1.1 subunits against all other genes in DepMap identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis.
Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of neuroblastoma.
Nathaniel W. Mabe. Therapeutic targeting of PRC1 complexes to induce neuroblastoma differentiation [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B010.
Nathaniel W. Mabe· Clinical Cancer Research· 0 citations
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved outcomes in EGFR-mutant lung adenocarcinoma (LUAD), yet acquired resistance to the third-generation inhibitor osimertinib remains inevitable. Although metabolic reprogramming is increasingly recognized as a driver of therapeutic resistance, the epigenetic consequences of lactate accumulation and their functional relevance in osimertinib resistance are poorly understood. Here we report that osimertinib-resistant LUAD cells exhibit enhanced glycolytic flux, increased intracellular lactate levels, and elevated histone H4 lysine 8 lactylation (H4K8la). Integrative transcriptomic analysis revealed significant enrichment of cell-cycle–associated pathways in resistant tumors, despite downregulation of canonical Cyclin B1 and Cyclin D1. Among the upregulated genes, GAS2L3 emerged as a prominent candidate. Genome-wide CUT&Tag profiling demonstrated enrichment of H4K8la at the GAS2L3 promoter, which was confirmed by ChIP–qPCR. Functionally, GAS2L3 overexpression accelerated S/G2–M progression and promoted proliferation under drug pressure, whereas its silencing induced cell-cycle arrest and restored osimertinib sensitivity both in vitro and in xenograft models. Notably, resistant cells displayed elevated P53 expression without induction of its canonical effector P21, indicating checkpoint uncoupling and a noncanonical mode of cell-cycle regulation. Mechanistically, glycolysis inhibition reduced H4K8la and GAS2L3 expression and partially re-sensitized resistant cells, while exogenous lactate restored H4K8la levels and resistance phenotypes, establishing a metabolically driven epigenetic circuit. Clinically, high GAS2L3 expression was associated with shorter progression-free survival in osimertinib-treated patients. Collectively, our findings identify a glycolysis–H4K8la–GAS2L3 axis that drives noncanonical cell-cycle reprogramming independently of classical Cyclin–CDK activation, thereby promoting acquired osimertinib resistance. These results uncover a metabolism-epigenetics–cell cycle interface that may represent a therapeutic vulnerability in EGFR-mutant LUAD.
Shu-Man Zhen, Xiao-Xue Bai, Shu-Tang Liu et al.· Cell Death Discovery· 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
Cervical cancer remains the fourth most common malignancy among women worldwide, and patients with advanced-stage disease continue to experience poor clinical outcomes despite the availability of targeted therapies. In this study, we investigated the epigenetic role of endothelial cell-specific molecule 1 (ESM1), a soluble proteoglycan, and established an oncogene whose regulatory mechanisms in cervical cancer remain largely unexplored. The epigenetic mechanisms underlying tumor progression remain incompletely understood. Here, we identify ESM1 as a critical epigenetic regulator of cervical cancer malignancy. Integrative analyses of public datasets and clinical specimens revealed that marked ESM1 overexpression correlated with adverse patient prognosis. Functional loss- and gain-of-function studies have demonstrated that ESM1 is essential for maintaining proliferative, clonogenic, migratory, and invasive phenotypes in cervical cancer cells. Transcriptomic profiling revealed that inhibitor of DNA binding 3 (ID3) is a direct downstream tumor suppressor repressed by ESM1. Mechanistically, ESM1 selectively upregulates DNA methyltransferase 3 A (DNMT3A) to induce promoter hypermethylation and transcriptional silencing of ID3. Pharmacological demethylation reactivates ID3 expression and attenuates metastatic capacity. In vivo xenograft and experimental metastasis models validated that ESM1 depletion significantly impaired tumor growth and lung metastasis while increasing ID3 expression. These findings identify the ESM1/DNMT3A/ID3 axis as a novel epigenetic driver of cervical cancer and a potential therapeutic target.
Chen-Lin Yu, Chia-Liang Lin, Hsiang-Lin Lee et al.· Cell Death Discovery· 0 citations