Search Results (105)

Metastasis is still the leading cause of cancer-related death. It happens when disseminated tumor cells (DTCs) successfully navigate a series of steps and adapt to the unique conditions of distant organs. In this review, key molecular and immune mechanisms that shape metastatic spread, long-term survival, and eventual outgrowth are examined, with a focus on how tumor-intrinsic programs interact with extracellular matrix (ECM) remodeling, angiogenesis, and immune regulation. Gene networks that sustain tumor-cell plasticity and invasion are described, including EMT-linked transcription factors such as SNAIL and TWIST, as well as broader transcriptional regulators like SP1. Also, how epigenetic mechanisms, such as EZH2 activity, DNA methylation, chromatin remodeling, and noncoding RNAs, lock in pro-metastatic states and support adaptation under therapeutic pressure. Finally, proteases and matrix-modifying enzymes that physically and biochemically reshape tissues, including MMPs, uPA, cathepsins, LOX/LOXL2, and heparinase, are discussed for their roles in releasing stored growth signals and building permissive niches that enable seeding and colonization. In parallel, immune-evasion strategies that protect circulating and newly seeded tumor cells are discussed, including platelet-mediated shielding, suppressive myeloid populations, checkpoint signaling, and stromal barriers that exclude effector lymphocytes. A major focus is metastatic dormancy, cellular, angiogenic, and immune-mediated, framed as a reversible survival state regulated by stress signaling, adhesion cues, metabolic rewiring, and niche constraints, and as a key determinant of late relapse. Tumor-specific metastatic programs across mesenchymal malignancies (osteosarcoma, chondrosarcoma, and liposarcoma) and selected high-burden cancers (melanoma, hepatocellular carcinoma, glioblastoma, and breast cancer) are highlighted, emphasizing shared principles and divergent organotropisms. Emerging therapeutic strategies that target both the “seed” and the “soil” are also discussed, including immunotherapy combinations, stromal/ECM normalization, chemokine-axis inhibition, epigenetic reprogramming, and liquid-biopsy-enabled minimal residual disease monitoring, to prevent reactivation and improve durable control of metastatic disease. Full article

Precision medicine has reshaped the clinical management of prostate cancer by integrating comprehensive genomic profiling, biomarker-driven patient stratification, and the development of molecularly targeted therapeutics. Advances in next-generation sequencing have uncovered diverse genomic alterations—including homologous recombination repair defects, MSI-H/MMRd, PTEN loss, BRCA1/BRCA2 mutations, ATM alterations, SPOP mutations, and molecular hallmarks of neuroendocrine differentiation—that now inform individualized treatment decisions. This review synthesizes established clinical evidence with emerging translational insights to provide an updated and forward-looking overview of precision oncology in prostate cancer. Landmark trials of PARP inhibitors and PSMA-targeted radioligand therapy have redefined treatment standards for biomarker-selected patients. Concurrently, efforts to optimize immune checkpoint inhibition, AKT pathway targeting, and rational combinations with androgen receptor pathway inhibitors continue to expand therapeutic possibilities. Rapidly evolving investigational strategies—including bipolar androgen therapy (BAT), immunotherapeutic approaches for CDK12-altered tumors, targeted interventions for SPOP-mutated cancers, and epigenetic modulation such as EZH2 inhibition for neuroendocrine prostate cancer—further illuminate mechanisms of tumor evolution, lineage plasticity, and treatment resistance. Integrating multi-omics technologies, liquid biopsy platforms, and AI-assisted imaging offers new opportunities for dynamic disease monitoring and biology-driven treatment selection. By consolidating current clinical practices with emerging experimental directions, this review provides clinicians and researchers with a comprehensive perspective on the evolving landscape of precision medicine in prostate cancer and highlights future opportunities to improve patient outcomes. Full article

We previously demonstrated that in BAP1-proficient pleural mesothelioma cells, CDKN2A is critical for mediating the response to selective EZH2 inhibition and highlighted a complex interplay between epigenetic regulation and the tumor immune microenvironment. In this study, we employed a quantitative proteomic mass spectrometry approach to assess alterations in protein expression following EZH2 inhibition in BAP1- and CDKN2A-proficient mesothelioma cells cultured as spheroids. Additionally, we analyzed extracellular vesicles (EVs), which were isolated through tangential flow filtration. Flow cytometric analysis and co-culture systems were used to characterize the effects of EVs on neutrophils. Upon EZH2 inhibition, we demonstrated RAB27b and CD63 upregulation and increased release of extracellular vesicles. We found that a brief exposure to EVs derived from EZH2 inhibitor-treated cells skewed naïve neutrophils toward a pro-tumor phenotype characterized by high levels of PD-L1 and MSLN (Mesothelin) expression on the surface. These EV-elicited neutrophils suppressed T cell proliferation while enhancing tumor cell growth. Moreover, we observed changes in the EV cargo derived from EZH2 inhibitor-treated spheroids. Our findings highlight the significant role of EVs in creating an immunosuppressive microenvironment, and underscore the urgent need for further investigation into the regulation of neutrophil biology and function in the PM. Full article

Background: Cervical cancer remains a major global health burden, and treatment failure due to radioresistance and secondary drug resistance severely limits clinical outcomes. Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator implicated in tumor progression. This study aimed to determine whether EZH2-mediated PTEN silencing drives afatinib resistance via AKT activation in radiation-resistant cervical cancer cells. Methods: A radioresistant cervical cancer cell line (HeLaR) was established following cumulative irradiation (70 Gy). Cell viability, clonogenic survival, methylation-specific PCR (MSP), chromatin immunoprecipitation (ChIP), and Western blot analyses were conducted. EZH2 (Dznep; tazemetostat), PI3K, and AKT inhibitors were tested in combination with afatinib. A xenograft mouse model was used for in vivo validation. Results: HeLaR cells exhibited upregulation of EZH2 and H3K27me3, downregulation of PTEN, and sustained AKT activation. EZH2 inhibition restored PTEN expression, attenuated AKT phosphorylation, and re-sensitized cells to afatinib. MSP and ChIP confirmed EZH2-mediated PTEN promoter silencing. PI3K inhibition reproduced these effects, whereas ERK inhibition had minimal impact. In xenograft models, combined treatment with Dznep and afatinib significantly suppressed tumor growth compared to single agents. Conclusions: EZH2-driven PTEN suppression promotes AKT-dependent afatinib resistance in radiation-resistant cervical cancer. Targeting the EZH2–PTEN–AKT axis may provide a potential therapeutic approach to mitigate combined radioresistance and chemoresistance in recurrent cervical cancer, although further preclinical and clinical validation is required. Full article

Background: A range of cancer cells are significantly inhibited by FTY720. It is unknown, nevertheless, how FTY720 influences the onset of non-small cell lung cancer (NSCLC). Using bioinformatics techniques, we analyzed and the possible molecular mechanisms and targets of FTY720 for the treatment of NSCLC. Methods: DEGs (Differentially expressed genes) were acquired by differential analysis of the dataset GSE10072. Obtained FTY720 target genes and NSCLC disease genes from databases such as Swiss-TargetPrediction and GeneCard. Subsequently, target and disease genes, as well as DEGs, were merged for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, gene ontology (GO), and protein interaction analysis. The overlapping genes of DEGs and target genes, and disease genes were also obtained separately and subjected to survival as well as expression analyses. We constructed the regulatory network of miRNAs and transcription factors (TFs) on hub genes. Finally, the immune cell association of hub genes was evaluated using the ssGSEA method, molecular docking of FTY720 to hub genes was carried out utilizing Autodock, and molecular dynamics simulations were conducted. Results: In this study, 444 DEGs, 232 target genes of FTY720, and 466 disease genes were obtained. Moreover, a total of 1062 genes were obtained by removing duplicate values after merging, among which PIK3R1, Akt1, and S1PR1 had the highest DEGREE values in the protein interactions network, and these genes were primarily enriched in MAPK, PI3K-Akt signaling pathways, with the PI3K-Akt signaling pathway being the most prominent. Among the overlapping genes, three potential targets of FTY720 for NSCLC treatment were found: S1PR1, ZEB2, and HBEGF. ZEB2 and S1PR1 were determined to be hub genes and to significantly affect NSCLC prognosis by survival analysis. Furthermore, hsa-miR-132-3p, hsa-miR-192-5p, and hsa-miR-6845-3p were strongly associated with FTY720 for the treatment of NSCLC; CTBP1 (carboxy-terminal binding protein 1), EZH2 (protein lysine N-methyltransferase), and ZNF610 (zinc-finger protein 610) may all influence the expression of ZEB2 and S1PR1. Hub genes had a substantial negative link with memory B cells and a significant positive correlation with memory CD8 T cells and Th17 helper T cells. The molecular docking and kinetic simulation results of FTY720 with the two hub genes indicate that the protein-ligand complex has good stability. Conclusion: Our research indicates that FTY720 may inhibit NSCLC via possible targets ZEB2 and S1PR1, further laying the theoretical foundation for the utilization of FTY720 in NSCLC treatment. Full article

Breast cancer (BC) is the most common malignancy and the second-leading cause of cancer-related mortalities in women. Epidemiological studies suggested the reduced BC incidence in Mediterranean populations due to the daily consumption of diets rich in extra-virgin olive oil (EVOO). EVOO secoiridoid phenolics are widely known for their positive outcomes on multiple cancers, including BC. The current study investigates the suppressive effects of individual and combined EVOO phenolics for BC progression and motility. Screening of a small library of EVOO phenolics at a single dose of 10 µM against the viability of the BC cell lines ZR-75-1 (luminal A) and MDA-MB-231 (triple negative BC, TNBC) identified oleocanthal (OC) and ligstroside aglycone (LA) as the most active hits. Screening of EVOO phenolics for BC cells migration inhibition identified OC, LA, and the EVOO lignans acetoxypinoresinol and pinoresinol as the most active hits. Combination studies of different olive phenolics showed that OC combined with LA had the best synergistic inhibitory effects against the TNBC MDA-MB-231 cells migration. A combination of 5 µM of each of OC and LA potently suppressed the migration and invasion of the MDA-MB-231 cells versus LA and OC individual therapies and vehicle control (VC). Animal studies using the ZR-75-1 BC cells orthotopic xenografting model in female nude mice showed significant tumor progression suppression by the combined OC-LA, 5 mg/kg each, ip, 3X/week treatments compared to individual LA and OC treatments and VC. The BC suppressive effects of the OC-LA combination were associated with the modulation of SMYD2–EZH2–STAT3 signaling pathway. A metastasis–clonogenicity animal study model using female nude mice subjected to tail vein injection of MDA-MB-231-Luc TNBC cells also revealed the effective synergy of the combined OC-LA, 5 mg/kg each, compared to their individual therapies and VC. Thus, EVOO cultivars rich in OC with optimal LA content can be useful nutraceuticals for invasive hormone-dependent BC and TNBC progression and metastasis. Full article

Curcumin-mediated anti-cancer properties have been correlated with the inhibition of oncogenic molecules such as mutp53 and c-Myc. Their targeting is therapeutically significant, as p53, following point mutations, can acquire oncogenic functions, and c-Myc overexpression, due to translocations, point mutations, protein/protein interactions, or epigenetic modifications, plays a central role in cancer cell proliferation and metabolic reprogramming, particularly in colorectal cancer. In a previous study, we showed that curcumin strongly downregulated mutp53 while activating wtp53 and reduced the expression of methyltransferases such as EZH2, G9a, and MLL-1 in colon cancer cells. Based on this background, here we investigated whether the dysregulation of such methyltransferases could correlate with the effect observed on p53. We also explored whether these epigenetic changes could affect c-Myc expression in these cells. By Western blot analysis and RT-qPCR, we found that the downregulation of EZH2; G9a; and, to a lesser extent, KDM1, which was also reduced by curcumin, correlated with the decrease in mutp53 and that the reduction of EZH2 and KDM1 correlated with the activation of wtp53. Regarding c-Myc, we unveiled the occurrence of a positive feedback loop between it and MLL-1, which was inhibited by curcumin, independently of the p53 status. In conclusion, this study provides new insights into the therapeutic potential of curcumin, which involves its properties to act as an epigenetic modulator and target key molecules in colon cancer cells. Full article

We have previously demonstrated the ability of inhibitors of LSD1 and HDAC1 to block rod degeneration, preserve vision, maintain transcription of rod photoreceptor genes, and downregulate transcripts involved in cell death, gliosis, and inflammation in the mouse model of Retinitis Pigmentosa (RP), rd10. To extend our findings, we tested the hypothesis that this effect was due to altered chromatin structure by using a range of inhibitors of chromatin condensation to prevent photoreceptor degeneration in the rd10 mouse model. We used inhibitors for both G9A/GLP, which catalyzes methylation of H3K9, and EZH2, which catalyzes trimethylation of H3K27, and compared them to the actions of inhibitors of LSD1 and HDAC. All the inhibitors are likely to decondense chromatin and all preserve, to different extents, retinas from degeneration in rd10 mice, but they act through different metabolic pathways. One group of inhibitors, modifiers for LSD1 and EZH2, demonstrate a high level of maintenance of rod-specific transcripts, activation of Ca²⁺ and Wnt signaling pathways with the inhibition of antigen processing and presentation, immune response, and microglia phagocytosis. Another group of inhibitors, modifiers for HDAC and G9A/GLP, work through upregulation of NGF-stimulated transcription, while downregulating genes belong to immune response, extracellular matrix, cholesterol signaling, and programmed cell death. Our results provide robust support for our hypothesis that inhibition of chromatin condensation can be sufficient to prevent rod death in rd10 mice. Full article

Epigenetic abnormalities play a critical role in colon carcinogenesis, making them a promising target for therapeutic interventions. In this study, we demonstrated that curcumin reduces colon cancer cell survival and that a decrease in lysine methylation was involved in such an effect. This correlated with the downregulation of methyltransferases EZH2, MLL1, and G9a, in both wild-type p53 (wtp53) HCT116 cells and mutant p53 (mutp53) SW480 cells, as well as SET7/9 specifically in wtp53 HCT116 cells. The effects induced by curcumin were more pronounced in wtp53 cells, where it induced a stronger apoptosis and ferroptosis. Interestingly, curcumin also reduced mutp53 expression, suggesting that it could enhance the efficacy of other therapies, particularly in overcoming drug resistance mechanisms associated with mutp53. For instance, in this study, we show that curcumin sensitized SW480 cells to SET7/9 inhibition by sinefungin, further supporting its potential as a combinatorial therapeutic agent. However, although to a lesser extent, curcumin also impaired cell survival in HCT 116 p53 null cells, suggesting that other molecular pathways or factors, beyond p53, may be involved in curcumin-induced cytotoxicity. Full article

Background/Objectives: CSCs are critical drivers of the tumor and stem cell phenotypes of glioblastoma (GBM) cells. Chromatin modifications play a fundamental role in driving a GBM CSC phenotype. The goal of this study is to further our understanding of how stem cell-driving events control changes in chromatin architecture that contribute to the tumor-propagating phenotype of GBM. Methods: We utilized computational analyses to identify a subset of clinically relevant genes that were predicted to be repressed in a Polycomb repressive complex 2 (PRC2)-dependent manner in GBM upon induction of stem cell-driving events. These associations were validated in patient-derived GBM neurosphere models using state-of-the-art molecular techniques to express, silence, and measure microRNA (miRNA) and gene expression changes. Advanced Poly(β-amino ester) nanoparticle formulations (PBAEs) were used to deliver miRNAs in vivo to orthotopic human GBM tumor models. Results: We show that glioma stem cell (GSC) formation and tumor propagation involve the crosstalk between multiple epigenetic mechanisms, resulting in the repression of the miRNAs that regulate PRC2 function and histone H3 lysine 27 tri-methylation (H3K27me3). We also identified miR-217-5p as an EZH2 regulator repressed in GSCs and showed that miR-217-5p reconstitution using advanced nanoparticle formulations re-activates the PRC2-repressed genes, inhibits GSC formation, impairs tumor growth, and enhances the effects of ionizing radiation in an orthotopic model of GBM. Conclusions: These findings suggest that inhibiting PRC2 function by targeting EZH2 with miR-217-5p advanced nanoparticle formulations could have a therapeutic benefit in GBM. Full article

Polycomb repressive complex 2 (PRC2) is known to regulate gene expression and chromatin structure as it methylates H3K27, resulting in gene silencing. Studies have shown that PRC2 has dual functions in oncogenesis that allow it to function as both an oncogene and a tumor suppressor. Because of this, nuanced strategies are necessary to promote or inhibit PRC2 activity therapeutically. Given the therapeutic vulnerabilities and associated risks in oncological applications, a structured literature review on PRC2 was conducted to showcase similar cofactor competitor inhibitors of PRC2. Key inhibitors such as Tazemetostat, GSK126, Valemetostat, and UNC1999 have shown promise for clinical use within various studies. Tazemetostat and GSK126 are both highly selective for wild-type and lymphoma-associated EZH2 mutants. Valemetostat and UNC1999 have shown promise as orally bioavailable and SAM-competitive inhibitors of both EZH1 and EZH2, giving them greater efficacy against potential drug resistance. The development of other PRC2 inhibitors, particularly inhibitors targeting the EED or SUZ12 subunit, is also being explored with the development of drugs like EED 226. This review aims to bridge gaps in the current literature and provide a unified perspective on promising PRC2 inhibitors as therapeutic agents in the treatment of lymphomas and solid tumors. Full article

Enhancer of zeste homolog 2 (EZH2) is a methyltransferase involved in cell cycle regulation, cell differentiation, and cell death and plays a role in modulating the immune response. Although it mainly functions by catalyzing the tri-methylation of H3 histone on K27 (H3K27), to inhibit the transcription of target genes, EZH2 can directly methylate several transcription factors or form complexes with them, regulating their functions. EZH2 expression/activity is often dysregulated in cancer, contributing to carcinogenesis and immune escape, thereby representing an important target in anti-cancer therapy. This review summarizes some of the mechanisms through which EZH2 regulates the expression and function of tumor suppressor genes and oncogenic molecules such as STAT3, mutant p53, and c-Myc and how it modulates the anti-cancer immune response. The influence of posttranslational modifications on EZH2 activity and stability and the possible strategies leading to its inhibition are also reviewed. Full article

Background: Schwann cells (SCs) and their plasticity contribute to the peripheral nervous system’s capacity for nerve regeneration after injury. The Egr2/Krox20 promoter antisense RNA (Egr2-AS) recruits chromatin remodeling complexes to inhibit Egr2 transcription following peripheral nerve injury. Methods: RNA-seq and ATAC-seq were performed on control cells, Lenti-GFP-transduced cells, and cells overexpressing Egr2-AS (Lenti-AS). Egr2 AS-RNA was cloned into the pLVX-DsRed-Express2-N1 lentiviral expression vector (Clontech, Mountain View, CA, USA), and the levels of AS-RNA expression were determined. Ezh2 and Wdr5 were immunoprecipitated from rat SCs and RT-qPCR was performed against AS-Egr2 RNA. ChIP followed by DNA purification columns was used to perform qPCR for relevant promoters. Hi-C, HiC-DC+, R, Bioconductor, and TOBIAS were used for significant and differential loop analysis, identifications of COREs and CORE-promotor loops, comparisons of TF activity at promoter sites, and identification of site-specific TF footprints. OnTAD was used to detect TADs, and Juicer was used to identify A/B compartments. Results: Here we show that a Neuregulin-ErbB2/3 signaling axis mediates binding of the Egr2-AS to YY1^Ser184 and regulates its expression. Egr2-AS modulates the chromatin accessibility of Schwann cells and interacts with two distinct histone modification complexes. It binds to EZH2 and WDR5 and enables targeting of H3K27me3 and H3K4me3 to promoters of Egr2 and C-JUN, respectively. Expression of the Egr2-AS results in reorganization of the global chromatin landscape and quantitative changes in the loop formation and contact frequency at domain boundaries exhibiting enrichment for AP-1 genes. In addition, the Egr2-AS induces changes in the hierarchical TADs and increases transcription factor binding scores on an inter-TAD loop between a super-enhancer regulatory hub and the promoter of mTOR. Conclusions: Our results show that Neuregulin-ErbB2/3-YY1 regulates the expression of Egr2-AS, which mediates remodeling of the chromatin landscape in Schwann cells. Full article

Background: Mucosal melanoma (MM) is epidemiologically, biologically, and molecularly distinct from cutaneous melanoma. Current treatment strategies have failed to significantly improve the prognosis for MM patients. This study aims to identify therapeutic targets and develop combination strategies by investigating the mechanisms underlying the tumorigenesis and progression of MM. Methods: We analyzed the copy number amplification of enhancer of zeste homolog 2 (EZH2) in 547 melanoma patients and investigated its correlation with clinical prognosis. Utilizing cell lines, organoids, and patient-derived xenograft models, we assessed the impact of EZH2 on cell proliferation and sensitivity to ferroptosis. Further, we explored the mechanisms of ferroptosis resistance associated with EZH2 by conducting RNA sequencing and chromatin immunoprecipitation sequencing. Results: EZH2 copy number amplification was closely associated with malignant phenotype and poor prognosis in MM patients. EZH2 was essential for MM cell proliferation in vitro and in vivo. Moreover, genetic perturbation of EZH2 rendered MM cells sensitized to ferroptosis. Combination treatment of EZH2 inhibitor with ferroptosis inducer significantly inhibited the growth of MM. Mechanistically, EZH2 inhibited the expression of Krüpple-Like factor 14 (KLF14), which binds to the promoter of solute carrier family 7 member 11 (SLC7A11) to repress its transcription. Loss of EZH2 therefore reduced the expression of SLC7A11, leading to reduced intracellular SLC7A11-dependent glutathione synthesis to promote ferroptosis. Conclusion: Our findings not only establish EZH2 as a biomarker for MM prognosis but also highlight the EZH2-KLF14-SLC7A11 axis as a potential target for MM treatment. Full article

Background/Objectives: Methyltransferase EZH2-mediated H3K27me3 is involved in liver inflammation and fibrosis, but its role in hepatic metabolic derangements is not yet clearly defined. We investigated if a high-fat diet (HFD) induced early changes in EZH2 expression and H3K27 me3 in the liver of mice. Methods: Five-week-old mice were fed an HFD or a low-fat diet (Control) for 2 weeks (2 W) or 8 weeks (8 W). Body weight was recorded weekly. Glycemia and oral glucose tolerance were assessed at baseline and after 2 W–8 W. Finally, livers were collected for further analysis. Results: As expected, mice that received 8 W HFD showed an increase in body weight, glycemia, and liver steatosis and an impairment in glucose tolerance; no alterations were observed in 2 W HFD mice. Eight weeks of HFD caused hepatic EZH2 nuclear localization and increased H3 K27me3; surprisingly, the same alterations occurred in 2 W HFD mice livers, even before overweight onset. We demonstrated that selective EZH2 inhibition reduced H3K27me3 and counteracted lipid accumulation in HUH-7 cells upon palmitic acid treatment. Conclusions: In conclusion, we point to EZH2/H3K27me3 as an early epigenetic event occurring in fatty-acid-challenged livers both in vivo and in vitro, thus establishing EZH2 as a potential pharmacological target for metabolic derangements. Full article