Search Results (129)

Transposable elements (TEs) play important roles during development and disease, including through transcriptional activation of TE-associated genes during early human development. Moreover, based on the functional and epigenetic similarities between early development and cancer, TE-associated genes contribute not only to early human development, but frequently contribute to cancer progression. In this study, we hypothesised that recruitment of TE-associated genes during cancer onset occurs through epigenetic regulatory processes, especially involving DNA hypomethylation accompanied by transcriptional upregulation of early developmental pathways, such that, when reactivated inappropriately in later life, they may drive malignancy. It is unknown, however, to what extent DNA methylation changes are critically involved in the transcriptional activation of TE-associated genes. Accordingly, to investigate this we used the RepExpress tool to identify developmentally regulated TE-associated genes in placenta and human embryonic stem cells (hESCs), which we then investigated by targeted deep bisulfite sequencing (TDBS) to determine the methylation status of the identified TE-associated genes in placenta, somatic tissues, and melanoma cell lines. Outcomes suggest that DNA methylation may be one of the regulatory factors underscoring transcriptional activation of TE-associated genes, but that methylation is not necessarily the sole factor involved in regulating the transcriptional activation of TE-associated genes during malignant transformation. Full article

Dpep is a cell-penetrating peptide that targets transcription factors ATF5, CEBPB and CEBPD to selectively suppress growth and survival of diverse tumor cell types in vitro and in vivo. Due to these actions and its apparent safety, the peptide has potential as a cancer therapeutic. How Dpep might be combined with other anti-cancer agents to achieve synergistic efficacy and to overcome possible peptide resistance has not been assessed in depth. Based on prior work indicating that Dpep promotes apoptotic cancer cell death and up-regulates multiple pro-apoptotic and tumor suppressor genes, we studied combinations of Dpep with ABT-263, a pro-apoptotic BCL2 family inhibitor, and decitabine, a hypomethylating drug. Combining Dpep with each agent alone or together synergistically suppressed the growth of a range of solid and liquid tumor cell types. Moreover, the combinations synergistically inhibited the growth of cells lines that were selected either in vivo or in vitro for Dpep resistance. Finally, we tested the combination of Dpep with ABT-263 in a mouse melanoma xenograft model. The combination more effectively inhibited tumor growth than either agent alone and, in contrast to vehicle or ABT-263, produced a 40% durable survival rate. Taken together, these observations highlight potential drug partners for the therapeutic development of Dpep. Full article

Background/Objectives: VEXAS (Vacuoles, E1-Enzyme, X-linked, Autoinflammatory, and Somatic) syndrome is a recently described adult-onset autoinflammatory disorder. It is characterized by somatic mutations in the UBA1 gene, systemic inflammation, macrocytic anemia, cytopenias, and bone marrow vacuolization and frequently overlaps with Sweet’s syndrome, relapsing polychondritis, and myelodysplastic syndrome (MDS). Because treatment options are evolving, we reviewed the current and latest evidence of clinical features and therapeutic methods. Methods: A comprehensive literature review was conducted using PubMed and MEDLINE for studies published between 1 January 2020 and 1 July 2025. Search terms included “VEXAS” and “treatment.” Eligible publications comprised clinical trials, multicenter and observational studies, and case reports containing therapeutic data. Findings were analyzed narratively with emphasis on treatment response, steroid-sparing effects, survival outcomes, and molecular responses. Results: Glucocorticoids remain the first-line therapy for acute management; however, this comes with near-universal steroid dependence. DMARDs and TNF-α inhibitors showed limited benefits. IL-6 inhibitors and JAK inhibitors showed improvement in overall response, with JAK inhibitors demonstrating a superior effect. Ruxolitinib showed a higher complete response rate and transfusion independence compared to other JAK inhibitors. Hypomethylating agents, particularly azacitidine, improved hematologic responses in patients with co-existing MDS and reduced UBA1 variant allele burden. Allogeneic hematopoietic stem cell transplantation may be the only current curative method, though with notable transplant-related mortality. Conclusions: JAK inhibitors and hypomethylating agents offer promising disease-modifying potential, while transplant may provide curative intent in selected patients. Ongoing clinical trials are taking place to dictate the treatment direction of VEXAS syndrome. Full article

Background: Aberrant protein O-fucosylation mediated by protein O-fucosyltransferase 1 (POFUT1), has emerged as a hallmark of tumorigenesis that regulates key signaling pathways, including Notch, which is frequently dysregulated in cancers. Protein O-fucosylation, catalyzed by POFUT1, regulates Notch signaling and has been implicated in individual cancers, but its pan-cancer expression patterns, clinical significance, and relationship to tumor immunity remain incompletely characterized. Methodology: We conducted a multi-omics bioinformatics analysis using TCGA and other public datasets to evaluate POFUT1 expression across 33 cancer types (n > 10,000). Differential expressions, tumor stage correlations, and survival outcomes were assessed. Immune cell infiltration was estimated using SangerBox and TIMER algorithms, while promoter methylation patterns were analyzed through UALCAN. Functional enrichment and protein–protein interaction networks were constructed to elucidate functional mechanism. Western blot validation in prostate and ovarian cancer cell lines confirmed our computational analysis. Results: POFUT1 showed significant overexpression in 16 of 33 cancer types (FDR-adjusted p < 0.05), with the highest elevation in BRCA (breast invasive carcinoma; log2FC = 2.31) and LUAD (lung adenocarcinoma; log2FC = 2.1). A high POFUT1 expression correlated with poor overall survival in eight cancer types (HR range: 1.8–3.2, p < 0.01) and disease-free survival in seven cancers. POFUT1 levels positively correlated with myeloid-derived suppressor cells (MDSCs) infiltrating in 15 cancer types, while inversely correlated with natural killer T (NKT) cells presence in 15 cancers (mean R = −0.34, p < 0.05), indicating an association with immunosuppressive microenvironments. Promoter hypomethylation in tumors suggested epigenetic dysregulation as a potential driver of its overexpression. Western blot analysis confirmed POFUT1 protein upregulations in prostate and ovarian cancer cell lines (1.7–2.1-fold. p < 0.01), corroborating transcriptomic findings. Conclusion: This pan-cancer study establishes POFUT1 as a critical oncogenic factor linked to aggressive disease, immune evasion, and poor prognosis. Its consistent overexpression and functional impact highlight its potential as a biomarker and target for anticancer therapy. While these computational findings require experimental validation, POFUT1 emerges as a candidate biomarker warranting functional studies and potential therapeutic targeting. Full article

Background/Objectives: Epigenetic modifications, particularly DNA methylation, contribute to tumor progression and therapy resistance. Guadecitabine, a hypomethylating agent (HMA), has shown promising clinical activity when combined with carboplatin in preclinical models. We evaluated the combination of guadecitabine with carboplatin as a second-line treatment for extensive-stage small-cell lung cancer (SCLC; NCT03913455), one of the deadliest malignancies. Here, we report methylome changes in peripheral blood mononuclear cells (PBMCs) collected at baseline and during treatment from patients on the trial. Methods: PMBC DNA was analyzed using Infinium HumanMethylationEPIC v1.0 bead chips. Data were processed, and differentially methylated positions (DMPs) were identified and analyzed for pathway enrichment using bioinformatic approaches, and immune deconvolution analyses were conducted to investigate the impact on immune cell composition. Results: Direct comparison of PBMCs between cycle 2 day 5 (C2D5; post-treatment) vs. cycle 1 day 1 (C1D1; pre-treatment) revealed a greater number of hypomethylated DMPs (380 DMPs in C2D5 vs. C1D1 PBMCs; p < 0.05, |β| > 20%). Moreover, when first compared with normal PBMCs from cancer-free controls, the number of hypomethylated DMPs was even greater in C2D5 than in C1D1 (1771 vs. 237 DMPs, respectively; p < 0.05, |β| > 20%). Long interspersed nucleotide elements-1 (LINE-1) were significantly hypomethylated in PBMCs after HMA treatment (C2D5 vs. C1D1). Pathway analysis of hypomethylated DMPs revealed significant alterations in key signaling pathways, including NF-κB, Rho GTPase, and pulmonary fibrosis in C1D1 vs. C2D5. Normal PBMCs to C1D1 PBMCs revealed changes in IL-3 signaling, Fcγ receptor-mediated phagocytosis, and molecular mechanisms of cancer. Deconvolution analysis revealed a greater percentage of monocytes in C1D1 vs. normal PBMCs; after HMA treatment, percentages of monocytes and B cells decreased, while the eosinophil percentage increased in C1D1 vs. C2D5. Conclusions: HMA treatment has a global impact on PBMC methylomes in cancer patients. DNA methylation changes were associated with biological pathways related to PBMC function, and shifts in distinct immune cell populations were observed. Full article

Recent implementations with novel target drugs of the hypomethylating agent/venetoclax doublet challenge our treatment approach in acute myeloid leukemia patients ineligible for intensive chemotherapy. Given the doublets’ efficacy, associations of agents based on the disease’s biology to the doublet backbone are leading to novel triplet (or more) combinations. In the present review mainly FLT3, IDH and KMT2A are discussed as possible targets in this context. These triplets do not only have efficacy in relapsed/refractory patients but also in treatment-naïve patients. Results from concluded and ongoing clinical trials, as well as real-world experiences, report high efficacies competing with intensive chemotherapy. For instance, the azacytidine/venetoclax/gilteritinib triplet as first-line is reported to induce a complete remission rate with and without incomplete recovery (CR/CRi) of 96%, with 90% of responders achieving minimal residual negativity. Once a stable CR was obtained, 47% of patients who were initially considered too frail for intensive chemotherapy were able to undergo allogeneic stem cell transplantation. However, there are still open questions and challenges regarding toxicity, post-remission therapy, and overall treatment duration. The present review will not only present the specific potency of these arising triplets, but also discuss their challenges and limitations, based on currently available data. Besides regimens containing approved inhibitors, triplets with next-generation inhibitors, including completely orally administered triplet regimens, are also summarized. Their promising results are leading to advanced phase clinical studies by international consortia and collaborative groups, aiming to further refine their clinical management. Full article

Neural progenitor cell (NPC) fate decisions are governed by transcriptional and signaling programmes, yet the epigenetic mechanisms stabilising early neuronal versus glial lineage trajectories remain unresolved. Here, DNA methylation landscapes in two widely used human NPC models—ReNcell VM (RVM) and ReNcell CX (RCX)—were examined under several different culture conditions to define regulatory pathways shaping lineage specification. Exploratory analyses revealed that the ReNcell lines exhibited methylation similar to primary glial populations rather than neuronal subtypes, with RCX cells positioned further along a maturation trajectory and RVM cells retaining a multipotent state. RCX cultures displayed hypomethylation of neuronal markers (DCX, ENO2, MAP2), whereas RVM cultures showed consistent GFAP hypomethylation, indicative of glial or early progenitor identity. Signaling pathways regulating lineage commitment were highlighted, including TGFβ, Wnt, and Notch signaling. Within the Notch pathway, RCX cells exhibited higher gene expression of NOTCH2 and JAG ligands, consistent with active lateral induction and a developmentally advanced state. In contrast, RVM cells exhibited higher DLL1 and NOTCH1 expression, supporting lateral inhibition and cellular heterogeneity. Knockdown of syndecan-4 (SDC4) revealed opposing effects on Notch activity. Together, these findings established DNA methylation as a determinant of lineage-specific signaling in human NPCs. Full article

The escalating incidence of colorectal cancer (CRC), particularly the alarming rise in early-onset cases, necessitates a paradigm shift from a purely genetic perspective to a broader investigation of promising pathways. This review explores the “nutri-epigenetic” interface, positioning liquid biopsy as a critical technology for translating dietary impacts into actionable clinical biomarkers. We contrast the molecular consequences of the Western dietary pattern, characterized by methyl-donor deficiency and pro-inflammatory metabolites, with the protective mechanisms of the Mediterranean diet. Mechanistically, we detail how Western-style diets drive a specific “epigenetic double-hit”: promoting global DNA hypomethylation (destabilizing LINE-1) while paradoxically inducing promoter hypermethylation of critical tumour suppressors (MLH1, APC, MGMT) and silencing tumour-suppressive microRNAs (miR-34b/c, miR-137) via methylation of their encoding genes. Conversely, we highlight the capacity of Mediterranean bioactive compounds (e.g., resveratrol, curcumin, butyrate) to inhibit DNA methyltransferases and restore epigenetic homeostasis. Bridging molecular biology and clinical utility, we demonstrate how these diet-sensitive signatures, specifically circulating methylated DNA and dysregulated microRNAs, can be captured via liquid biopsy. We propose that these circulating analytes serve as dynamic, accessible biomarkers for monitoring the molecular progression toward a carcinogenic state, thereby establishing a novel framework for personalized risk stratification and validating the efficacy of preventive nutritional strategies. Full article

Graves’ disease (GD) and Thyroid Eye Disease (TED) are autoimmune disorders characterized by significant heterogeneity in treatment response. Up to 50% of GD patients relapse after antithyroid drug (ATD) withdrawal, and a substantial portion of TED patients (20–50%) are resistant to first-line glucocorticoid (GC) therapy. This review evaluates the current evidence on epigenetic modifications as predictive biomarkers to guide personalized treatment. We synthesized recent findings (up to 2025) from PubMed, focusing on DNA methylation and microRNAs (miRNAs). For GD, ATD relapse risk is linked to a persistent “epigenetic memory” in T cells, notably the hypomethylation of Th17-associated genes. Circulating miRNA signatures, including miR-346, miR-23b-5p, and miR-92a-3p, also show promise in predicting remission. For TED, GC sensitivity is strongly correlated with specific circulating miRNAs. High pre-treatment levels of miR-146a predict a positive response (100% positive predictive value), while low levels of miR-224-5p predict non-responsiveness. While DNA methylation is confirmed in TED pathogenesis, its predictive role is unstudied. Major research gaps persist, particularly the near-total absence of data on histone modifications as predictive markers and the lack of epigenetic predictors for new biologics treatments, which currently rely on genetic or pharmacokinetic markers. Epigenetic biomarkers represent a promising frontier for stratifying patients and optimizing therapeutic strategies in Graves’ autoimmunity. Full article

Background: BCAR3 has been implicated in various cancers, yet its role in thyroid cancer (TC) remains unclear. This study aimed to investigate the methylation status, functional effects, and underlying mechanisms of BCAR3 in TC. Methods: BCAR3 methylation was analyzed using matrix-assisted laser desorption/ionization–time-of-flight (MALDI-TOF) mass spectrometry in 422 TC and 371 benign thyroid nodule samples. Expression levels were assessed via immunohistochemistry, qPCR, and Western blot. Functional assays including proliferation, migration, and invasion were performed after BCAR3 knockdown. Rescue experiments using a PI3K activator were conducted to examine pathway mechanisms. Results: BCAR3 was significantly hypomethylated in TC compared to benign tissues (p < 0.001), with CpG_6 most strongly associated with TC risk (odds ratio, OR = 1.73, p < 0.001). Notably, BCAR3 hypomethylation was more pronounced in cases with larger tumor size and advanced disease stage. Furthermore, BCAR3 methylation showed differential patterns across TC subtypes, with medullary thyroid carcinoma exhibiting the lowest methylation levels. BCAR3 expression was upregulated in TC tissues and cell lines (p < 0.05). Mechanistically, BCAR3 knockdown reduced phosphorylation of AKT/mTOR and altered expression of epithelial-to-mesenchymal transition (EMT) marker, characterized by an increase in E-cadherin and decreases in Vimentin and N-cadherin, and consequently suppressed proliferation, migration, and invasion (p < 0.05). Rescue experiments with a PI3K activator showed a trend towards restoration of these effects, although not to the level of the control groups. Conclusions: BCAR3 hypomethylation contributes to TC cells’ proliferation, migration, and invasion by promoting AKT/mTOR activation and EMT. These findings highlight the potential of BCAR3 methylation as both a biomarker and a therapeutic target in TC. Full article

Estrogen (E2, 17β estradiol) is recognized for its regulatory role in numerous genes associated with energy metabolism and for its ability to disrupt mitochondrial function in various cancer types. However, the influence of E2 on the metabolism of colorectal cancer (CRC) cells remains largely unexplored. In this study, we examined how E2 affects mitochondrial function and energy production in CRC cells, utilizing two distinct CRC cell lines, HCT-116 and SW480. Cell viability, mitochondrial function, and the expression of several genes involved in oxidative phosphorylation (OXPHOS) were assessed in estrogen receptor α (ERα)-expressing and ERα-silenced cells treated with increasing concentrations of E2 for 48 h. Our results indicated that the cytotoxicity of E2 against CRC cells is mediated by the E2/ERα complex, which induces disturbances in mitochondrial function and the OXPHOS pathway. Furthermore, we identified two novel targets, RPS2 and TMEM177, which displayed overexpression, hypomethylation, and a negative association with ERα expression in CRC tissue. E2 treatment in CRC cells reduced the expression of both targets through promoter hypermethylation. Treatment with 5-Aza-2-deoxycytidine increased the expression of RPS2 and TMEM177. This epigenetic effect disrupts the mitochondrial membrane potential (MMP), resulting in decreased activity of the OXPHOS pathway and inhibition of CRC cell growth. Knockdown of RPS2 or TMEM177 in CRC cells resulted in anti-cancer effects and disruption of MMP and OXPHOS. These findings suggest that E2 exerts ERα-dependent epigenetic reprogramming that leads to significant mitochondria-related anti-growth effects in CRC. Full article

Extrachromosomal circular DNA (eccDNA) has been recognized as a key player in tumorigenesis and progression. However, eccDNA transcriptional regulatory mechanisms under DNA damage in cancer remain poorly characterized. Here, we used doxorubicin to induce DNA damage in the hepatocellular carcinoma cell line HepG2 and performed Circle-seq to profile eccDNAs before and after the damage. We observed a significant increase in the number, length, and chromosomal distribution density of eccDNAs following DNA damage. RNA-seq revealed that the expression of genes carried on eccDNA was positively correlated with eccDNA copy number under DNA damage. Further ATAC-seq profiling identified distinct chromatin characteristics at eccDNA breakpoint regions compared to other regions of eccDNA and linear genomic regions. Additionally, eccDNAs generated under DNA damage preferentially originated from linear genomic regions characterized by low GC content and hypomethylation. Finally, by integrating Hi-C and H3K27ac ChIP-seq, we uncovered that eccDNAs with mobile enhancer activity (ME-eccDNAs) display significantly enhanced chromatin interactions and H3K27ac enrichment after DNA damage. Overall, our findings systematically elucidate the DNA damage-driven mechanisms underlying eccDNA biogenesis, chromatin characteristics and transcriptional regulation in HCC HepG2 cells. Full article

This study aimed to evaluate the effects of melatonin supplementation during bovine in vitro embryo production (IVEP) on embryonic development and quality, oxidative stress, lipid metabolism, mitochondrial activity, gene expression, DNA methylation patterns, and cryotolerance. Four treatments were tested: control (without melatonin), melatonin at maturation (IVM + Mlt), culture (IVC + Mlt), and both treatments (IMV/IVC + Mlt). Melatonin significantly improved blastocyst rate and developmental kinetics on D7, reduced ROS and intracellular lipid levels, and increased mitochondrial activity. The most significant effects were observed in the IVC + Mlt group. Melatonin modulated antioxidant (SOD1, Cat, and GSS) and epigenetic (TET1, TET3, and DNMT3A) genes, and although it did not alter lipid gene expression, it reduced lipid content. Methylation analysis showed hypomethylation patterns in repetitive regions (Satellite I and LINE-1), which were even more pronounced in the melatonin-treated groups. However, no significant differences were observed between treatments in terms of cryotolerance or apoptosis rates. These findings suggest that melatonin exerts positive multifactorial effects, regardless of the supplementation stage. In particular, its addition during the IVC phase appears to provide greater benefits to embryos by improving their quality. Full article

Cervical cancer remains the fourth most common cancer among women globally, disproportionately impacting low- and middle-income countries despite the existence of HPV vaccines. While DNA methylation has been studied extensively as a biomarker, other epigenetic mechanisms remain underexplored. This scoping review aims to report such underexplored epigenetic biomarkers linked to cervical cancer, shifting the focus beyond global nuclear DNA methylation. Literature searches were performed using Google Scholar via Publish or Perish software including studies published until January 2025. Our review focused on mitochondrial DNA, non-coding RNA, histone modifications, and repetitive elements. Mitochondrial DNA methylation has been proposed as a cervical cancer biomarker, although supporting evidence is limited. Histone modifications are more consistently reported to be involved both in cervical cancer onset and aggressiveness. Similarly, aberrant expression of lncRNAs, circRNAs, miRNAs, and piRNAs has been associated with poor prognosis. Finally, hypomethylation in repetitive elements such as LINE-1 and Alu is often observed in cervical cancer, contributing to genomic instability and tumorigenesis. Highlighting these alternative epigenetic mechanisms, our review emphasizes the importance of expanding biomarker discovery beyond the traditional nuclear DNA methylation. Understanding these mechanisms may improve early detection and personalized disease management strategies for cervical cancer. Full article

DNA methylation holds promise for the early detection of tissue damage, making it crucial for identifying polycyclic aromatic hydrocarbon (PAH)-associated epigenetic biomarkers in childhood asthma. Sulforaphane (SFN), as a potential epigenetic modulator, can alleviate the adverse effects of environmental pollutants. This study quantified serum PAHs in 370 children via gas chromatography–mass spectrometry, assessed the methylation of target genes using bisulfite sequencing PCR (BSP), and performed mediation analysis to estimate the mediating effects of methylation levels between PAHs and childhood asthma. Murine models exposed to PAHs prenatally or postnatally, with offspring challenged with ovalbumin (OVA), were analyzed for lung DNA methylation. In vitro, HBE cells and HBSMCs treated with benzo(a)pyrene (BaP) and/or SFN were tested for inflammatory cytokines, methylation-related enzymes, and matrix metallopeptidase 9 (MMP9) modifications. The results showed total PAHs were associated with childhood asthma, with mediating effects of long interspersed nuclear element-1 (LINE-1) methylation. Prenatal PAH exposure enriched differentially methylated genes in the extracellular matrix (ECM)-receptor interaction pathway, while postnatal exposure enriched those in purine metabolism, and postnatal exposure also elevated Mmp9 expression via hypomethylation. BaP increased the expression of interferon gamma (IFN-γ), interleukin-4 (IL-4), interleukin-17A (IL-17A), transforming growth factor beta 1 (TGF-β), and ten-eleven translocation methylcytosine dioxygenases (TETs), and it upregulated MMP9 via enhancer hypomethylation and H3K27ac enrichment, while SFN reversed these effects by downregulating histone methyltransferase (HMT), leading to reduced H3K4me1 and subsequent H3K27ac depletion, thus suppressing MMP9 transcription. This study demonstrates that DNA methylation mediates PAH–childhood asthma associations, with distinct patterns in different exposure windows; MMP9 could serve as a crucial target for epigenetic modification during lung inflammation induced by PAH exposure, and SFN reverses PAH-induced epigenetic changes, aiding prevention strategies. Full article