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PubMed2026

A tunable, ultrasensitive threshold in enzymatic activity governs the DNA methylation landscape.

DNA methylation is a widely studied epigenetic mark, affecting gene expression and cellular function at multiple levels. DNA methylation in the mammalian genome occurs primarily at cytosine-phosphate-guanine (CpG) dinucleotides, and patterning of the methylation landscape (i.e., the presence or absence of CpG methylation at a given genomic location) exhibits a generally bimodal distribution. Although much is known about the enzymatic writers and erasers of CpG methylation, it is not fully understood how these enzymes, along with genetic, chromatin, and regulatory factors, control the genome-wide methylation landscape. In this study, methylation is analyzed at annotated CpG islands (CGIs) and independent CpGs as a function of their proximity to other CpG substrates. Analysis is aided by a computationally efficient stochastic mathematical model of methylation dynamics, enabling parameterization from data. We find that methylation exhibits a switch-like dependence on local CpG density with a threshold of 7-8 CpGs per 100 bp and a Hill coefficient of 4-5. The threshold and steepness of the switch is modified in cell lines in which key enzymes are knocked out. Modeling further elucidates how enzymatic parameters, including catalytic rates and lengthscales of inter-CpG interaction, tune the properties of the switch. Together, the results support a model in which competition between opposing TET1-3 demethylating enzymes and DNA methyltransferases (DNMT3A/B) results in an ultrasensitive switch, analogous to the protein phosphorylation switch (termed "zero-order ultrasensitivity"). Our study provides insight to the mechanisms underlying establishment and maintenance of bimodal DNA methylation landscapes, and further provides a flexible pipeline for gleaning molecular insights to the cellular methylation machinery across cell-specific, epigenomic data sets.

DNA Methylation↗
PubMed2026

Epigenetic regulation of kidney development.

The methylation or demethylation of genomic DNA at specific locations and the diverse array of post-translational modifications of histones associated with genomic DNA are collectively known as epigenetic modifications, so-called because they affect chromatin structure but do not affect the actual DNA sequence of the genome. Nevertheless, post-translational modifications of histones, including methylation, acetylation, phosphorylation and ubiquitination, as well as the methylation and subsequent de-methylation of genomic DNA, can profoundly affect gene expression. Nowhere has the study of epigenetically regulated gene expression had such impact as on our understanding of organism development. In the developing kidney, epigenetic-based regulation affects the cell fate decisions of stem-like nephron progenitor cells (NPCs). Changes in chromatin accessibility at the loci of genes associated with NPC self-renewal and nephron differentiation - in part driven by transcription factors known to regulate kidney development - affect the differentiation of NPCs into precursors of the nephron such as the pretubular aggregate and renal vesicle, and the subsequent differentiation of various segments of the mature nephron. Epigenetic mechanisms also contribute to the process of NPC ageing and the cessation of nephrogenesis, with consequences for nephron endowment and kidney function.

Epigenesis, Genetic↗
PubMed1979

Studies on histones and non-histone proteins from rats treated with dimethylnitrosamine.

A study has been made of the histone and non-histone chromosomal proteins of rat liver after treatment in vivo with dimethylnitrosamine (DMN) (2 mg/kg). DMN was found not to affect histone turnover, as measured by 3H-labelled amino-acids incorporation. A decrease was observed in specific activity of the histones with time after injection of [14C]DMN or [14C]-formate and this was attributable to demethylation of both abnormal and normal methylation sites in these proteins. In the case of the non-histone proteins, DMN was found to increase greatly the turnover of those non-histone proteins loosely associated with chromatin DNA and RNA; turnover of those non-histone proteins tightly bound to chromatin DNA and RNA was unaffected. Demethylation of both normal and abnormal methylation sites was found to take place from both non-histone protein fractions. In the case of the loosely bound non-histone proteins a lower rate of demethylation was observed after DMN treatment.

Animals↗
PubMed2026

The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.

PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (&#x2265;45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.

Humans↗
PubMed2026

Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple-Negative Breast Cancer to Doxorubicin.

Doxorubicin remains an important component of chemotherapy for triple-negative breast cancer (TNBC), yet chemoresistance severely limits its clinical efficacy. Here, we identify Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) as an epigenetically silenced gene that critically regulates doxorubicin response. Integrative analyses of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and clinical cohorts reveal that high TNFRSF19 expression predicts superior pathological complete response and improved survival in doxorubicin-treated TNBC patients. Mechanistically, TNFRSF19 binds the kinase domain of TGFBR1 via its intracellular domain, disrupting TGFBR1-SMAD3 complex formation and thereby inhibiting SMAD3 phosphorylation, nuclear translocation, and transcriptional activation of PTEN-induced putative kinase 1 (PINK1). This suppresses PINK1/Parkin-mediated mitophagy, contributing to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and amplified DNA damage upon doxorubicin treatment. Notably, TNFRSF19 is downregulated in TNBC due to DNA hypermethylation, and decitabine restores its expression via promoter demethylation, thereby enhancing the therapeutic efficacy of doxorubicin in vitro and in vivo. Collectively, these findings establish TNFRSF19 as a critical epigenetic regulator of mitophagy, highlighting its potential as a predictive biomarker for doxorubicin response and a therapeutic target for sensitizing TNBC to doxorubicin.

DNA methylation↗
PubMed2026

DNA methylation as a driver of lung fibroblast senescence in COPD.

Cellular senescence is increasingly recognized as a hallmark of chronic obstructive pulmonary disease (COPD), with higher levels in lung fibroblasts from COPD patients. Upon senescence, both hypomethylation and hypermethylation have been described but not in COPD-derived fibroblasts yet. This study investigated whether altered DNA methylation can be a driver of fibroblast senescence in COPD. Genome-wide gene expression and DNA methylation data were generated from primary lung fibroblasts of 11 COPD stage IV patients and 10 matched controls. Gene expression of six well-known senescence genes was compared between COPD and control. COPD-associated senescence genes were correlated with their related CpG sites in an expression quantitative trait methylation (eQTM) analysis. Methylation levels of significant eQTMs were compared between COPD and control fibroblasts. A causal relationship between altered DNA methylation and senescence was validated in 5-Aza-2'-deoxycytidine (5-Aza-2'-dC)-treated primary lung fibroblasts. Gene expression of CDKN1A, CDKN2A, and CDKN2B was higher, while LMNB1 expression was lower in COPD-derived fibroblasts compared to controls. A total of 19 eQTMs were found for the COPD-associated senescence genes CDKN1A (9), CDKN2A (1), and LMNB1 (9). Among these, seven CpG sites (4 for CDKN1A and 3 for LMNB1) exhibited differential methylation between COPD and control. Treatment with 5-Aza-2'-dC led to global demethylation and increased senescence and, importantly, confirmed the association between senescence and hypomethylation of the COPD-associated CpG site cg04924375. Altered DNA methylation is linked to fibroblast senescence in COPD, and seven CpG sites are identified as potential epigenetic regulators of the senescence genes CDKN1A and LMNB1.NEW & NOTEWORTHY This study identifies DNA methylation as a mechanistic contributor to lung fibroblast senescence in chronic obstructive pulmonary disease (COPD). By integrating DNA methylation data with the transcriptomic data of senescence-related genes, we uncovered seven COPD-associated CpG sites linked to the senescence regulators CDKN1A and LMNB1. Pharmacological demethylation induces fibroblast senescence and is consistent with a functional role for hypomethylation at cg04924375, providing new insight into epigenetic regulation of cellular senescence in COPD lung fibroblasts.

Humans↗
PubMed2025

Rescue of imprinted genes by epigenome editing in human cellular models of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genomic imprinting disorder caused by the loss of function of the paternal chromosome 15q11-13, resulting in a spectrum of symptoms associated with hypothalamic dysfunction. PWS patients lack the expression of paternally expressed genes (PEGs) in the 15q11-13 locus but possess an epigenetically silenced set of these genes in the maternal allele. Thus, activation of these silenced genes can serve as a therapeutic target for PWS. Here, we leverage CRISPR-based epigenome editing system to modulate the DNA methylation status of the PWS imprinting control region (PWS-ICR) in induced pluripotent stem cells (iPSCs) derived from PWS patients. Successful demethylation in the PWS-ICR restores the PEG expression from the maternal allele and reorganizes the methylation patterns in other PWS-associated imprinted regions beyond the PWS-ICR. Remarkably, these corrected epigenomic patterns and PEG expression are maintained following the differentiation of these cells into hypothalamic organoids. Finally, the single-cell transcriptomic analysis of epigenome-edited organoids demonstrates a partial restoration of the transcriptomic dysregulation observed in PWS. This study highlights the utility of epigenome editing technology as a therapeutic approach in addressing PWS and potentially other imprinting disorders.

Prader-Willi Syndrome↗
PubMed2025

Integrating advanced analytical methods to assess epigenetic marks affecting response to hypomethylating agents in higher risk myelodysplastic syndrome.

BACKGROUND: Patients with higher-risk (HR) myelodysplastic syndrome (MDS), ineligible for allogeneic hematopoietic stem cell transplantation (alloHSCT), require prompt therapeutic interventions, such as treatment with hypomethylating agents (HMAs) to restore normal DNA methylation patterns, mainly of oncosuppressor genes, and consequently to delay disease progression and increase overall survival (OS). However, response assessment to HMA treatment relies on conventional methods with limited capacity to uncover a wide spectrum of underlying molecular events. METHODS: We implemented liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess 5' methyl-2' deoxycytidine (5mdC), 5' hydroxy-methyl-2'-deoxycytidine (5hmdC) levels and global adenosine/thymidine ([dA]/[T]) ratio in bone marrow aspirates from twenty-one HR MDS patients, pre- and post-HMA treatment. Additionally, targeted methylation analysis was performed by interpretation of NGS-methylation (MeD-seq) data obtained from the same patient cohort. RESULTS: LC/MS-MS analysis revealed a significant hypomethylation status in responders (Rs), already established at baseline and a trend for further DNA methylation reduction post-HMA treatment. Non-responders (NRs) reached statistical significance for DNA hypomethylation only post-HMA treatment. The 5hmdC epigenetic mark was approximately detected at 37.5-40% among NRs and Rs, implying the impairment of the natural active demethylation pathway, mediated by the ten-eleven (TET) 5mdC dioxygenases. R and NR subgroups displayed a [dA]/[T] ratio&#x2009;<&#x2009;1 (0.727&#x2009;-&#x2009;0.633), supporting high frequences of 5mdC transition to thymidine. Response to treatment, according to whole genome MeD-seq data analysis, was associated with specific, scattered hypomethylated DMRs, rather than presenting a global effect across genome. MeD-seq analysis identified divergent epigenetic effects along chromosomes 7, 9, 12, 16, 18, 21, 22, X and Y. Within statistically significant selected chromosomal bins, genes encoding for proteins and non-coding RNAs with reversed methylation profiles between Rs and NRs, were highlighted. CONCLUSIONS: Implementation of powerful analytical tools to identify the dynamic DNA methylation changes in HR MDS patients undergoing HMA therapy demonstrated that LC-MS/MS exerts high efficiency as a broad-based but rapid and cost-effective methodology (compared to MeD-seq) to decode different perspectives of the epigenetic background of HR MDS patients and possess discriminative efficacy of the response phenotype to HMA treatment.

Humans↗
PubMed2025

CtBP1-LSD1 complex drives ErbB2 activation via H3K9me2 demethylation in DRGs during paclitaxel-induced neuropathic pain.

Paclitaxel (PTX), a commonly utilized chemotherapy drug, is linked to peripheral neuropathy, which limits dosing and significantly affects patients' quality of life. C-terminal binding protein 1 (CtBP1) is a transcriptional coregulator that participates in epigenetic gene regulation, but its role in PTX-induced neuropathic pain remains unclear. In this study, the role of CtBP1 in PTX-induced neuropathic pain is examined, with a focus on its epigenetic regulation in the dorsal root ganglia (DRGs). PTX administration markedly increased CtBP1 protein levels in DRG neurons, which coincided with the development and continuation of mechanical allodynia and thermal hyperalgesia in rat models. Our findings also revealed that CtBP1 interacts with the histone demethylase LSD1-a regulator of H3K9me2-at ErbB2 promoter sites in DRG neurons. PTX treatment increased CtBP1 protein levels, which subsequently induced LSD1 expression and decreased H3K9me2 protein levels at the ErbB2 promoter, indicating epigenetic activation of ErbB2 signaling in DRG neurons implicated in neuropathic pain. Reducing either CtBP1 or LSD1 expression reversed ErbB2 upregulation and attenuated PTX-induced pain sensitivity. These results suggest that the CtBP1-LSD1 complex epigenetically increases ErbB2 expression in DRG neurons, contributing to PTX-induced neuropathy. Targeting the CtBP1-LSD1 pathway could represent a promising therapeutic strategy for the treatment of chemotherapy-induced neuropathic pain.

Animals↗
PubMed1979

A quantitative microdensitometric and autoradiographic study of the effect of 4'-demethyl-epipodophyllotoxin-beta-D-thenylidene glucoside (VM-26) on the cell cycle of cultured fibroblasts.

The effect of 4'-demethyl-epipodophyllotoxin-beta-D-thenylidene glucoside (VM-26) , a semi-synthetic derivative of podophyllotoxin, on the cell cycle was studied with chick embryo fibroblasts cultivated in vitro. DNA, RNA and protein content, as well as NADH-diaphorase activity were determined by quantitative microdensitometry and cytofluorometry. The incorporation of [3H]thymidine and [3H]leucine into DNA and proteins were analysed by autoradiography. These metabolic data correlated with morphological observation showed that VM-26 blocks the cell cycle at different moments of its kinetics depending on both the dose and the time exposure. NADH-diaphorase activity is the first to be affected, then biochemical changes (involving the metabolism of RNA and proteins) and morphological alterations (especially of mitochondria) follow. This suggests that VM-26 may act primarily upon the mechanism of respiration of the cell.

Animals↗
PubMed2024

Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes.

To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n&#xa0;= 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6&#xa0;months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation.

Adult↗
PubMed2026

Epigenetic activation of NK-cell effector programs and caspase-8-dependent apoptosis mediates the antitumor activity of LGP in NSCLC.

BACKGROUND: Effective activation of natural killer (NK) cell cytotoxicity and caspase-8-dependent extrinsic apoptosis remains a major challenge in non-small cell lung cancer (NSCLC). Epigenetic mechanisms regulating NK cell function within the tumor microenvironment are poorly understood and rarely targeted therapeutically. METHODS: The antitumor activity of Li-Ginseng Powder (LGP), a specifically processed Panax ginseng formulation enriched in rare ginsenosides (Rh4, Rg3, Rg5, Rk1, and Rk3), was evaluated in human lung cancer A549&#x202f;cells and A549 xenograft mouse models. NK cell infiltration and activation were assessed by flow cytometry, immunoblotting, and immunohistochemistry. Whole-genome bisulfite sequencing (WGBS) was performed to analyze DNA methylation changes. The effects of LGP ginsenosides (LGG) on tumor cell apoptosis and death receptor signaling were examined in vitro. RESULTS: LGP significantly suppressed tumor growth and enhanced systemic and intratumoral NK cell activation. Promoter demethylation of NK cell effector genes, including Ncr1, Gzmb, Nktr, and Itgal, was associated with increased NK cell infiltration and activation, elevated granule-mediated cytotoxicity, and enhanced IFN-&#x3b3; signaling. In parallel, LGP treatment induced caspase-8-dependent apoptosis associated with increased expression of membrane death receptors, their ligands, FADD, and procaspase-8 in tumor tissues. In vitro, LGG upregulated these apoptosis-initiating proteins and triggered caspase-8 activation in A549&#x202f;cells independent of promoter methylation changes. Collectively, these immune-associated and tumor-intrinsic responses contributed to robust tumor suppression with a favorable systemic safety profile. CONCLUSIONS: LGP exerts dual antitumor effects characterized by enhanced NK-cell activation and increased sensitivity of tumor cells to caspase-8-dependent extrinsic apoptosis. These coordinated immune-associated and apoptosis-sensitizing effects underscore the therapeutic potential of LGP for the treatment of NSCLC.

DNA methylation↗
PubMed1979

Role of dimethylnitrosamine-demethylase in the metabolic activation of dimethylinitrosamine.

In vivo administration to rats of the mixed-function oxidase modifiers 3-methylcholanthrene (MC), pregnenolone-16 alpha-carbonitrile (PCN) or beta-naphthoflavnoe (beta-f) inhibits the hepatic microsome-catalyzed in vitro binding of dimethylnitrosamine (DMN) to DNA. This parallels their effect on DMN-demethylase I, regarded to be the sole activating step in DMN carcinogenesis and fails to account for the previously observed anomaly that MC and PCN inhibit, while beta-NF enhances, the hepatocarcinogenic activity of DMN. The in vitro binding of DMN is clearly dependent on microsomes and NADPH, and is strongly enhanced by soluble cytoplasmic proteins; the presence of the latter has no effect. however, on the relative response to pretreatment by the modifiers. In mice beta-NF enhances and PCN inhibits DMN-demethylase I; beta-NF has no effect on either the cytochrome P-450 level or on the LD50, while PCN strongly increases the cytochrome P-450 level but without influencing the LD50. Neither of the two modifiers has any effect in mice on the host-mediated mutagenicity of DMN in a dose-response study, except for the highest dose of DMN (200 mg/kg) where PCN pretreatment significantly enhanced mutagenicity. To account for the anomalous observations, other potential pathways of DMN metabolism have been explored. Whole rat liver nuclei or isolated nuclear membrane fractions contain no DMN-demethylase or diethylnitrosamine-deethylase activity. In a microsomal mixed-function amine-oxidase assay system neither purified enzyme preparations nor whole microsomes catalyze NADPH oxidation in the presence of DMN as substrate. In addition, the purified enzyme does not catalyze formaldehyde production in the DMN-demethylase assay system. Benzylamine, a typical inhibitor of mitochondrial monoamine oxidase (MAO), is a potent inhibitor of DMN-demethylase activity, but microsomes are devoid of MAO activity. Furthermore, purified MAO has no DMN-demethylase activity. The differential effect of modifiers on the carcinogenicity of DMN probably involves pathways other than DMN metabolism.

Biotransformation↗
PubMed1978

The effects of aminoethyl phosphonic acid on hepatic microsomal drug metabolism and ultrastructure of normal and cholesterol fed rats.

The effects of parenteral administration of aminoethyl phosphonic acid (AEP) on the liver microsomal drug metabolism and ultrastructure were studied in normal and 1% cholesterol-fed albino rats. AEP administration to rats fed a stock-diet resulted in decreased demethylation of aminopyrine with a concomitant fall in cytochrome P-450 level. Aniline hydroxylation remained unaltered. AEP injection to cholesterol-fed rats, caused marked reduction in both aminopyrine demethylation and aniline hydroxylation, with a significant increase in cytochrome P-450 level. AEP injection to both control and cholesterol-fed animals produced a modest increase in Bilirubin UDP-glucuronyl transferase. RNA:DNA ratio showed remarkable elevation in rats fed the cholesterol diet with AEP injection. AEP injection caused an atypical smooth endoplasmic reticulum and a marked loss of nuclear euchromatin. Effect of AEP was more pronounced in rats receiving the cholesterol-diet. AEP administration thus induces structural and drug metabolic enzyme alteration in liver.

Aminoethylphosphonic Acid↗
PubMed2025

Novel insights into hypoxia-driven transcriptomic and epigenetic landscapes in grade 3 meningioma.

BACKGROUND: Meningiomas are among the most prevalent central nervous system (CNS) tumors, with up to 20% of cases exhibiting recurrence or aggressive behavior. Hypoxia is a key driver of malignant transformation and therapeutic resistance, yet its molecular basis in meningioma remains poorly understood. METHODS: We conducted integrative transcriptomic and epigenomic profiling of IOMM-Lee cells (grade 3 meningioma) cultured under hypoxic (0.2% O&#x2082;) and normoxic conditions. RNA-sequencing and Illumina MethylationEPIC v2.0 data were analyzed in R using DESeq2 and minfi, respectively. Functional enrichment, transcription-factor binding analysis, and pathway mapping (clusterProfiler, enrichR) were performed. Findings were cross-validated in public meningioma datasets, in Indian meningioma patient cohort and cell line via RT-qPCR, and azacytidine-based demethylation assay. Functional role of the candidate gene was elucidated in vitro via cellular assays. RESULTS: Hypoxia triggered a canonical HIF1A-driven transcriptional program activating glycolytic and angiogenic pathways while downregulating genes associated with DNA repair and replication in meningioma. Several differentially expressed genes (DEGs) were identified as known oncogenes, tumor-suppressors, or associated with immune regulation and stemness. Promoter motif analysis identified HIF1, SP1, TP53, BRCA1, and E2F1 as enriched transcriptional regulators. We validated hypoxia and HIF1-mediated regulation of some of the top DEGs. DNA-methylation analysis revealed epigenetic silencing of RTN4IP1 and ZBTB7C under hypoxia, reversible upon azacytidine treatment. Integrative comparison with patient datasets highlighted SLITRK2, PDE4C, SGCD, and LRP1B as hypoxia-responsive genes associated with poor prognosis. Several hypoxia-regulated genes also showed significant correlation with known hypoxia biomarkers, VEGFA and CA9. IGFBP3 and NDRG1 were among the top hypoxia-associated upregulated genes, and IGFBP3 expression was linked to advanced meningioma grades. Knockdown of IGFBP3 via siRNA in hypoxia-treated IOMM-Lee cells was associated with reduced cell proliferation and migration. CONCLUSIONS: This study presents the first integrated transcriptomic&#x2013;epigenomic landscape of hypoxia in grade 3 meningioma, uncovering regulatory networks and candidate biomarkers with prognostic and therapeutic potential. These findings provide a foundation for future translational studies targeting hypoxia-driven tumor progression in meningioma.

Humans↗
PubMed1978

Dietary lipotropes, hepatic microsomal mixed-function oxidase activities, and in vivo covalent binding of aflatoxin B1 in rats.

Weanling male Sprague-Dawley rats were fed either a nutritionally complete synthetic diet (Diet 1) or a diet marginally deficient in choline and methionine, and lacking folacin (lipotrope deficient, Diet 2) to determine the role of hepatic mixed-function oxidase metabolism of aflatoxin B1 (AFB1) in the Diet 2-induced enhancement of AFB1 hepatocarcinogenesis previously reported. Hepatic microsomal mixed-function oxidase activities, as assayed by ethylmorphine N-demethylation, ethoxycoumarin O-dealkylation, cytochrome c reduction, AFB1 metabolism, and cytochrome P-450 content, were all depressed by Diet 2. Furthermore, the proportion of an i.p. dose of AFB (1 mg/kg) that became covalently bonded to DNA and RNA was similarly reduced when measured 6 hr after administration. The formation of AFB1-protein adducts was not influenced by dietary treatment. The depression of DNA and RNA adduct formation in the Diet 2 animals was probably related to the lower mixed-function oxidase activities and not to an alteration of glutathione levels, which remained unchanged by dietary treatment. These results suggest that the marginally lipotrope-deficient diet does not enhance tumor formation through an increased microsomal activation of AFB1. Alternative hypotheses without data are suggested.

Aflatoxins↗
PubMed2026

Transcriptome-based epigenetic screening identifies DNA hypermethylation signatures as prognostic biomarkers in oral squamous cell carcinoma.

Promoter DNA hypermethylation is a key epigenetic mechanism of gene silencing in cancer, yet the DNA hypermethylome of oral squamous cell carcinoma (OSCC) and its prognostic relevance remain poorly characterized. Here, we systematically identified and validated novel hypermethylated genes with prognostic significance in OSCC using a genome-wide discovery and multi-platform validation strategy. Candidate genes were first identified by pharmacologic demethylation combined with RNA sequencing across OSCC cell lines, then validated by quantitative RT-PCR, methylation-specific PCR, and bisulfite sequencing in OSCC cell lines, normal oral mucosa, and primary OSCC tumors, with independent confirmation in the TCGA-HNSC dataset. Immunohistochemistry confirmed protein-level silencing, and Kaplan-Meier survival analysis assessed prognostic significance across both cohorts. This pipeline identified five candidate genes, GPX3, ANG, CTGF, GPRC5B, and BAMBI, exhibiting cancer-specific promoter hypermethylation associated with transcriptional and protein silencing in OSCC. Validation in oral cavity tumor samples extracted from the TCGA-HNSC dataset confirmed tumor-specific hypermethylation and revealed significant inverse correlations between methylation and expression for GPX3, GPRC5B, and CTGF. Notably, CTGF hypermethylation was independently associated with poor overall survival in both cohorts (institutional cohort, p=0.03; oral tumor subset from TCGA-HNSC, p=0.01), and a combined ANG+CTGF methylation signature showed superior and reproducible prognostic performance across both platforms. Pathway analysis linked these genes to epithelial-mesenchymal transition and interferon response signaling. This study establishes the first validated DNA methylation biomarker panel for OSCC prognosis, identifying CTGF hypermethylation as a robust prognostic driver with translational potential for clinical risk stratification.

Humans↗