This study aims to investigate the epigenetic regulation of TIPE3 in nasopharyngeal carcinoma (NPC) and its role in tumor progression, with a focus on enhancer elements and associated histone modifications, as well as the involvement of the Hedgehog signaling pathway.

Despite efforts to understand breast cancer biology, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional dysregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlie oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identified T-helper-inducing Poxviruses and Zinc-finger (POZ)/Krüppel-like factor (ThPOK, ZBTB7B), a CD4+ cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to an epithelial phenotype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/β-catenin target genes, and the pro-metastatic TGFβ pathway. Our study reveals ThPOK as a master transcription factor that restricts the acquisition of metastatic features in breast cancer cells.

Imatinib is a small molecule that inhibits receptor tyrosine kinases KIT and platelet-derived growth factor receptor α (PDGFRA). It was approved by the U.S. Food and Drug Administration (FDA) in 2002 for the treatment of advanced, unresectable gastrointestinal stromal tumours (GISTs). Since then, additional kinase inhibitors targeting multiple pathways have also been introduced. However, as treatment with imatinib is prolonged, its effectiveness gradually declines, with 50% of patients experiencing relapse within 2-5 years. This decline in effectiveness is largely attributed to the development of both initial and acquired resistance. Due to these mechanisms of resistance, many advanced GIST patients struggle to achieve long-term benefits from systemic treatment. This review aims to summarise the mechanisms of resistance to imatinib and their relationship with GIST molecular subtypes, while also exploring the latest strategies to overcome resistance. We discuss the alterations in signalling pathways following imatinib resistance, the disruption of autophagy and glycolysis, the role of microRNAs and immunotherapy in resistant GISTs, and combination therapies. Furthermore, we examine ongoing clinical trials and potential future therapies that could be integrated into clinical practice, offering guidance for new treatment strategies that aim to enhance the prognosis of advanced GIST patients.

Testicular germ cell tumors (TGCTs), though typically responsive to therapy, may rarely develop somatic-type malignancy (STM), a transformation associated with poor prognosis and chemoresistance. This study presents two cases of postpubertal-type teratoma with intestinal-type adenocarcinoma as STM, offering insights into their clinical, histopathological, immunophenotypic, and molecular profiles. The first patient, a 63-year-old male, presented with pulmonary and retroperitoneal metastases and underwent orchiectomy, revealing an intratesticular intestinal-type adenocarcinoma. Molecular testing confirmed 12p overrepresentation and pathogenic mutations in CTNNB1, STK11, and MDM2. The second patient, initially diagnosed at age 35 with a mixed TGCT, developed STM as a late recurrence 16 years post-orchiectomy, manifesting as a retroperitoneal mass with vertebral invasion. Histology again confirmed intestinal-type adenocarcinoma, and molecular testing revealed amplification of ERBB2, KRAS, along with mutations in TP53 and PIK3CA. Both cases were managed with capecitabine-oxaliplatin plus bevacizumab, followed by maintenance therapy, achieving disease stabilization for at least 9 months. These cases illustrate the diagnostic and therapeutic complexities of STM, particularly with adenocarcinoma morphology that may mimic primary gastrointestinal neoplasms. Accurate diagnosis required exclusion of alternate primary sites and demonstration of chromosome 12 aberrations using FISH and next-generation sequencing. Our findings emphasize the importance of long-term follow-up in TGCT patients, particularly those with teratomatous elements, and highlight the value of cytogenetic and molecular profiling in confirming STM and identifying potential therapeutic targets. Given the rarity of STM, especially in metastatic or recurrent settings, there is an urgent need for standardized diagnostic protocols and evidence-based treatment strategies. These cases support the use of tumor-specific chemotherapy regimens guided by the histological and molecular characteristics of STM.

This short review highlights recent findings related to transcription factor-mediated RNA polymerase II (Pol II) pause release at enhancers and its role in regulating cell identity. We discuss how the transcriptional state of Pol II, either paused or released, shapes enhancer-promoter interactions, thereby influencing gene expression programs that define cell identity. We further summarize current knowledge of DNA-binding transcription factors that regulate Pol II pause release at enhancers and explore how this process influences cell identity. We propose a novel concept of therapy-induced molecular amnesia, where temporary inhibition of enhancer-proximal Pol II pause release and enhancer RNA transcription affects enhancer-promoter interactions differently in distinct cellular contexts. In some contexts, preservation of enhancer-promoter interactions allows rapid transcriptional reactivation and maintenance of cell identity upon recovery. In other contexts, repeated inhibition of enhancer RNA transcription leads to the permanent dissociation of enhancer-promoter interactions and loss of cell identity. Our model suggests that manipulating Pol II pause release at enhancers could selectively reverse certain aggressive tumor cell identities, limit tumor cell plasticity, and improve therapy responsiveness.

The treatment of patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) whose disease progresses after tyrosine-kinase inhibitors (TKIs) treatment has become a research hotspot.

Gastric cancer immunotherapy, recognized as the fourth primary treatment modality after surgery, radiotherapy, and chemotherapy, encompasses strategies such as immune checkpoint inhibitors and cellular immunotherapy and provides new avenues for cancer control. Recent studies have revealed that non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, piRNAs, siRNAs, and circRNAs, drive the progression of gastric cancer primarily through three regulatory axes: epigenetic modification, transcriptional reprogramming, and tumor microenvironment remodeling. These processes are closely linked to tumor immunity and the efficacy of immunotherapy in gastric cancer (GC). Building on an overview of current immunotherapy regimens for GC, this review provides a comprehensive summary of the molecular mechanisms by which ncRNAs regulate immune cell infiltration, modulate immune checkpoints, and reshape the immunosuppressive microenvironment to influence immunotherapeutic outcomes. Furthermore, the potential translational applications of ncRNAs as prognostic biomarkers and therapeutic targets within the context of GC immunology are discussed. Collectively, these mechanistic insights and clinical perspectives offer a theoretical foundation for overcoming the limitations of current immunotherapy approaches and improving the long-term prognosis of patients with GC.

Current prognostic evaluation in melanoma primarily relies on traditional histopathological and clinical staging evaluation; however, these conventional approaches exhibit limited accuracy and fail to account for individual patient heterogeneity. To address these limitations, we developed a machine learning-driven prognostic signature, with the objectives of identifying pivotal biomarkers and establishing a precision medicine framework for prognostic assessment in melanoma management. Bulk RNA-seq data of 636 melanoma patients were obtained from TCGA and GEO databases, followed by univariate Cox regression to identify prognosis-associated genes. Intersecting results across cohorts identified consistently prognostic genes. Heterogeneity of the selected genes was assessed between primary and metastatic melanoma using scRNA-seq data. The consensus prognosis-related signature was developed by systematically integrating 101 machine learning algorithms, with model performance rigorously evaluated through multidimensional metrics. Finally, molecular experiments validated the prognostic relevance of the model's hub genes, and the biological role of CUL2 was investigated in melanoma. 53 protective prognosis-related genes (PRGs) were identified in melanoma. Single-cell analysis revealed elevated PRGs activity in primary melanoma tissues compared to metastatic lesions. A 14-gene consensus prognosis-related signature was developed using LASSO and RSF algorithms. The model achieved a C-index of 0.908 in the TCGA-SKCM cohort and a mean C-index of 0.758 across four independent validation cohorts. Furthermore, the model outperformed 19 existing prognostic models across multiple cohorts. This study developed a 14-gene consensus prognosis-related signature validated for robust prognostic performance across cohorts. CUL2, identified as a pivotal protective biomarker in melanoma, demonstrates potent tumour-suppressive activity through significant inhibition of proliferation and migration potential.

Glioma is the most prevalent primary brain tumor, causing significant mortality and morbidity. lncRNAs have great potential in tumor-targeted therapy, including for glioma via sponging microRNAs. Previous studies have shown that LINC00900 and miR-186-5p likely play a significant role in glioma progression. However, the relationship between them has not been elucidated. The purpose of this study was to explore the role of LINC00900 in the prognosis of gliomas and its underlying molecular mechanisms.

To evaluate the diagnostic performance of PAX1 gene methylation in the detection of cervical lesions and assess its potential clinical application in cervical cancer screening through both a single-centre study and a meta-analysis.

Renal cell carcinoma (RCC) accounts for 90% of adult renal cancer cases and is characterized by significant heterogeneity within its tumor microenvironment. This study tests the hypothesis that tumor-associated macrophages (TAMs) influence RCC progression and patient response to treatment by investigating the prognostic implications of TAM signatures. Utilizing independent single-cell RNA sequencing data from RCC patients, we developed eight distinct TAM signatures reflective of TAM presence. A LASSO Cox regression model was constructed to predict survival outcomes, evaluated using the TCGA dataset, and validated across independent RCC cohorts. Model performance was assessed through Kaplan-Meier survival plots, receiver operating characteristic (ROC) curves, and principal component analysis. Survival analysis demonstrated that specific TAM signature gene expressions serve as significant prognostic markers, identifying TAM signatures positively correlated with patient survival and macrophage infiltration. A 27-gene TAM risk model was established, successfully stratifying patients into risk categories, with low-risk patients showing improved overall survival. These findings provide insights into the role of TAMs in modulating the RCC tumor immune microenvironment and their impact on patient prognosis, suggesting that TAM-based signatures may serve as useful prognostic markers and potential targets to enhance RCC treatment strategies.

Breast cancer remains a leading cause of mortality among women despite advances in early detection and targeted therapies, underscoring the need for safer and more effective treatment options. Drug repurposing offers a promising strategy by leveraging existing pharmacological agents with established safety profiles. Desloratadine, a second-generation H1-histamine receptor antagonist widely prescribed for allergic conditions, has attracted interest in oncology because histamine signaling influences proliferation, angiogenesis, and immune responses, yet its anticancer potential remains poorly understood. In this study, we investigated its effects in MCF-7 breast cancer cells, which harbor wild-type TP53. Desloratadine inhibited cell viability in a dose-dependent manner, with an IC50 of 14.2 µg/mL. Mechanistic analyses revealed that growth inhibition was primarily mediated through apoptosis, confirmed by Hoechst 33342 staining, ROS generation, annexin V/PI staining, and caspase-dependent pathways. Gene expression profiling demonstrated upregulation of TP53, FAS, and BAX, alongside reduced PARP-1 and NF-κB expression, with no detectable STAT3 or BCL2 expression. Flow cytometry indicated accumulation of cells in the sub-G1 phase and G2/M arrest, consistent with apoptosis induction. Molecular docking further supported these findings, showing that Desloratadine binds with high affinity to p53 (-7.0 kcal/mol), FAS (-6.8 kcal/mol), and NF-κB (-6.5 kcal/mol), forming stabilizing hydrogen bonds and hydrophobic interactions aligned with the observed gene expression changes. To confirm the functional role of TP53, we generated CRISPR-Cas9 knockout MCF-7 cells. Compared with wild-type cells, these knockout cells displayed markedly reduced sensitivity to Desloratadine, with the IC50 shifting from 14.2 µg/mL to 36.4 µg/mL, demonstrating that p53 is a key mediator of the drug's cytotoxic effect. Collectively, these findings identify Desloratadine as a potential repurposed drug candidate for breast cancer therapy, acting at least in part through a p53-dependent apoptotic pathway.

Acute myeloid leukemia (AML) is a heterogeneous disease with an unmet need for novel therapeutic drugs. Previous studies have reported the upregulation of diacylglycerol kinases (DGKs) in AML. This study investigated the effects of ritanserin, a DGKα-specific inhibitor, and DGKζ-IN4 or BAY 2965501, DGKζ-selective inhibitors, on a panel of AML cell lines. Ritanserin induced apoptotic cell death across all tested models, whereas DGKζ inhibitors triggered both apoptosis and necrosis to variable extents, with HL-60 cells being the most responsive to both compounds. Drug sensitivity did not correlate with DGKα or DGKζ expression levels, indicating that additional factors may influence cellular susceptibility. THP-1 proteomic profiling revealed that ritanserin broadly downregulated proteins involved in antigen presentation, cell cycle and metabolism, while BAY 2965501 affected a smaller and distinct but functionally similar protein subset, implying different mechanisms of action. Gene silencing confirmed AML cell line-specific dependence on DGK isoforms: HEL cells were sensitive to DGKα knockdown, HL-60 to DGKζ silencing, whereas K562 and THP-1 were resistant to both. These findings indicate that DGKs targeting can effectively reduce AML cell viability. However, AML heterogeneity and the limited selectivity of current inhibitors underscore the need for predictive biomarkers and combinatorial strategies to translate DGK inhibition into effective therapy.

Targeted therapies, including treatment with inhibitors of BRAFV600 and MEK kinases, have improved outcomes in advanced melanoma. However, most patients relapse due to acquired resistance, underscoring the need for new drug targets. This study evaluated PRI-724, a CBP/β-catenin inhibitor, in patient-derived drug-naïve melanoma cells and their trametinib- or vemurafenib-resistant counterparts. While PRI-724 has demonstrated efficacy in preclinical models and clinical trials in different cancer types, its potential in melanoma has not been previously assessed. We found that treatment with PRI-724 downregulated survivin and other CBP/β-catenin target proteins, reduced invasiveness, and induced apoptosis in drug-naïve and trametinib- and vemurafenib-resistant cells. Trametinib-resistant melanoma cells showed the greatest sensitivity to PRI-724, indicating that CBP/β-catenin transcriptional activity may represent a new therapeutic vulnerability. Transcriptomic and immunoblotting analyses revealed the highest survivin levels in vemurafenib-resistant cells, which may underlie their reduced responsiveness to PRI-724. Bioinformatic analyses (TCGA and GSE50509) confirmed that a high survivin level predicts poor prognosis and reduced response to treatment. The results of the study point to the potential of PRI-724 as a chemotherapeutic agent for the treatment of melanoma. Its efficacy might depend on CBP/β-catenin transcriptional activity in melanoma cells, and further evaluation of this signaling with survivin as a biomarker is therefore warranted.

Besides genomic and proteomic analyses of bulk and individual cancer cells, cancer research focuses on the mechanical analysis of cancers, such as cancer cells. Throughout the oncogenic evolution of cancer, mechanical inputs are stored as epigenetic memory, which ensures versatile coding of malignant characteristics and a quicker response to external environmental influences in comparison to solely mutation-based clonal evolutionary mechanisms. Cancer's mechanical memory is a proposed mechanism for how complex details such as metastatic phenotypes, treatment resistance, and the interaction of cancers with their environment could be stored at multiple levels. The mechanism appears to be similar to the formation of memories in the brain and immune system like epigenetic alterations in individual cells and scattered state changes in groups of cells. Carcinogenesis could therefore be the outcome of physiological multistage feedback mechanisms triggered by specific heritable oncogenic alterations, resulting in a tumor-specific disruption of the integration of the target site/tissue into the overall organism. This review highlights and discusses the impact of the ECM on cancer cells' mechanical memory during their metastatic spread. Additionally, it demonstrates how the emergence of a mechanical memory of cancer can give rise to new degrees of individuality within the host organism, and a connection to the cancer entity is established by discussing a connection to the metastasis cascade. The aim is to identify common mechanical memory mechanisms of different types of cancer. Finally, it is emphasized that efforts to identify the malignant potency of tumors should go way beyond sequencing approaches and include a functional diagnosis of cancer physiology and a dynamic mechanical assessment of cancer cells.

RNA maturation, particularly splicing, depends on coordinated actions of RNA-binding proteins through post-transcriptional processing and constitutes a central mechanism of gene regulation. Aberrant splicing is associated with various diseases, including cancer. Here, we show that the CoREST complex, in coordination with c-MYC, transcriptionally regulates a subset of RNA processing genes, including those encoding essential small nuclear ribonucleoproteins (snRNPs) required for proper spliceosome function. Genetic depletion or the pharmacological inhibition of the CoREST complex in melanoma cells disrupted spliceosome activity, leading to widespread changes in alternative mRNA isoform expression and reduced cell viability. These splicing alterations were associated with changes in the 2'-O-methylation (Nm) of U1 snRNA, a modification critical for spliceosomal function. The ectopic expression of the nucleolar protein NOLC1, a downstream target of the CoREST complex and known for its role in ribosomal RNA processing, partially rescued viability, splicing patterns, and U1 snRNA methylation in CoREST-deficient melanoma cells. Conversely, NOLC1 depletion sensitized melanoma cells to the MEK inhibitor trametinib, a clinical drug approved for treating advanced melanoma. Together, these findings uncover a novel CoREST-NOLC1 axis which is a transcriptional regulatory mechanism playing a significant role in RNA splicing, highlighting that NOLC1 is a downstream effector of the CoREST complex and a potential therapeutic target for melanoma treatment.

The term extracellular vesicles (EVs) includes a variety of anucleated, non-self-replicative particles released by cells, whose cargo content is compartmentalized by a lipidic bilayer membrane and includes proteins, DNA, and RNA (both coding and non-coding) molecules. MicroRNAs (miRs) are small non-coding RNA involved in gene expression regulation that functionally participate in inter-cellular communication as EV cargo. Natural Killer (NK) cells are innate immunity lymphocytes specialized in the killing of cancer cells and virally infected cells. Increasing evidence shows that NK cell-derived EVs contribute to the anti-tumoral activity of NK cells and that such effects are, at least in part, mediated by the miR cargo of these EVs. Conversely, cancer cells release EVs whose cargo includes proteins and miRs that impair NK cell function. These interactions highlight a central role for EV miRs both in the NK-mediated cytotoxicity and as a major immune-escape mechanism for cancer cells, ultimately contributing to the overall success or failure of NK cells in eliciting their anti-tumoral activity.

Female infertility, affecting millions worldwide, involves complex molecular mechanisms such as chronic inflammation, impaired cellular death, and protein regulation. This study explores how the cytokine IL-6, the autophagy marker LC3, ubiquitination process, and three miRNAs, miR-146a-5p, miR-9-5p, and miR-9-3p, contribute to the control of ovarian function and female infertility. Two expression profile datasets (GSE199225 and GSE146856) were screened and downloaded from GEO. DEGs were screened using the GEO2R and ggVennDiagram tools. The three miRNAs were retrieved from datasets using the multiMiR tool, and IL6-targeted genes were retrieved from MSigDB. IL6 and miRNA interaction networks were constructed. Further, the cross-correlation of LC3 and ubiquitination with the DEGs associated miRNAs was demonstrated. Meanwhile, GO/KEGG pathway enrichment analyses and molecular network interaction analysis were performed. Lastly, immunohistochemistry and quantitative PCR (qPCR) were used to confirm the expression of IL6, LC3, and miRNA in ovarian endometrial tissues compared to control tissues. The results showed that IL-6 drives inflammation in conditions of PCOS and ovarian endometriosis, which then disrupts ovulation and embryo implantation. miR-146a-5p reduced inflammation by targeting the gene TRAF6, while miR-9-5p regulated protein degradation via SQSTM1. In agreement with the bioinformatic approach, experimental analysis revealed reduced IL6 protein expression in ovarian endometriosis tissues while the mRNA IL6 level was increased, suggesting the presence of post-transcriptional regulatory mechanisms that act to limit excessive inflammation, probably through miRNAs. Indeed, the levels of miR-146a-5, which plays a role in immune modulation and inflammatory signaling, were significantly upregulated. Interestingly, an alteration in autophagic markers revealed by elevated LC3 was also observed. Aligned with these experimental data, bioinformatic analysis showed that autophagy genes LC3 and ATG5 and ubiquitination processes were tightly linked to ovarian health, with disruptions accelerating follicle loss and oxidative damage. In conclusion, the results showed that IL-6, miRNAs, and autophagy processes work together to control inflammation and cellular repair in ovarian disorders. This study opens new avenues for targeted treatments to improve fertility outcomes by connecting molecular networks to clinical insights.

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management.

Endometrial carcinoma is the most frequent gynecologic malignancy in western countries. In recent years, mutations in CTNNB1 have been associated with worse prognosis in low-risk carcinomas. However, there is a lack of understanding of the proteomic implications of CTNNB1 mutations in this type of tumor. In this study, we performed shotgun proteomics using Formalin-Fixed Paraffin-Embedded (FFPE) tissue samples of CTNNB1 mutated and wild-type low-risk endometrial carcinomas. A publicly available proteomic and transcriptomic database was used to validate results. Differential protein expression and Gene Set Enrichment Analysis revealed dysregulation of pathways associated with cell keratinization, immune response modulation, and intracellular calcium regulation. CTNNB1 mutated tumors showed immune dysregulation at multiple levels including cytokine secretion, cell adhesion, and lymphocyte activation. These results were supported by tissue multiplex immunofluorescence analysis, demonstrating reduced CD8 tumor-infiltrating lymphocytes and different immune spatial interaction patterns. Intracellular calcium dysfunction was associated with key transcript dysregulation. We found an increased expression of CAMK2A and ROR2, suggesting a potential role for non-canonical Wnt pathway activation in CTNNB1 mutated tumors.