Histone H1.4 is a member of the linker histone H1 family, and its post-translational modifications (PTMs) are essential for its function. However, the role of H1.4 PTM in cancer development is not fully understood. Here, we report the discovery of a previously uncharacterized acetylation site at lysine 75 (K75) of H1.4 in non-small cell lung cancer (NSCLC). Point mutation of K75 with arginine (H1.4K75R) markedly suppressed cellular viability and migration in A549 and H1299 cells, and inhibit tumor growth in xenografts mouse models. Moreover, RNA-sequencing and Western Blot analyses revealed that H1.4K75 acetylation orchestrates dual regulatory effects, potentiating ERK1/2 signaling while repressing the p53 pathway. In summary, our studies show that H1.4K75 acetylation is essential for cell viability, migration and tumor growth in NSCLC, and may be a therapeutic target for NSCLC.

Epigenetic modifications play a critical role in regulating gene expression under various physiological and pathological conditions. Epigenetic modifications reprogramming is a recognized hallmark of aging and a key component of the aging clock used to differentiate between chronological and biological age. The potential for prospective diagnosis and regulatory capabilities position epigenetic modifications as an emerging drug target to extend longevity and alleviate age-related organ dysfunctions. In the past few decades, numerous preclinical studies have demonstrated the therapeutic potential of natural products in various human diseases, including aging, with some advancing to clinical trials and clinical application. This review highlights the discovery and recent advancements in the aging clock, as well as the potential use of natural products as anti-aging therapeutics by correcting disordered epigenetic reprogramming. Specifically, the focus is on the imbalance of histone modifications, alterations in DNA methylation patterns, disrupted ATP-dependent chromatin remodeling, and changes in RNA modifications. By exploring these areas, new insights can be gained into aging prediction and anti-aging interventions.

Triple-negative breast cancer, the most aggressive breast cancer with highest metastatic capacity and the worst prognosis, accounts for 15 % of breast cancer. According to prior studies, the natural active component genkwanin suppressed cell growth in estrogen-receptor-positive breast cancer. Nonetheless, its impact on triple-negative breast cancer and its target remains poorly understood.

To explore the effects of genkwanin and identify the direct targets and cellular mechanism of genkwanin in triple-negative breast cancer.

The effects of genkwanin were investigated in SUM-159PT and MDA-MB-231 cells. Direct target protein of genkwanin were identified by Quantitative proteomics. The in-vivo effect of genkwanin on triple-negative breast cancer was investigated using mouse models.

The anti-metastasis effects of genkwanin were investigated by individual cell-tracking assay and 3D-on top assay. Quantitative proteomics was used to identify the target of genkwanin and microscale thermophoresis ligand-binding assay was performed to further confirmed it. In-vitro and in-vivo extreme limiting diluting assays were performed to investigate the inhibitory effect of stemness. Lung metastasis mouse model was used to evaluate the anti-metastasis effects of genkwanin.

This study demonstrated that genkwanin could significantly attenuate migration and invasion in triple-negative breast cancer cells. Notably, genkwanin could efficiently modulate the stemness of breast cancer cells and improve its sensitivity to paclitaxel (PTX). Lysine demethylase 4C (KDM4C) was identified as the target of genkwanin and the in-vivo therapeutic effect of genkwanin was also confirmed in 4T1-luc lung metastasis model. Mechanically, genkwanin reduced KDM4C expression, which regulated the lysine demethylation of histone H3, thereby suppressing KLF14 transcription. KLF14 acts as a switch of lipid synthesis and regulates intracellular cholesterol levels, inhibiting cancer metastasis.

These results demonstrate genkwanin's therapeutic potential in triple-negative breast cancer and its effect on targeting metastasis.

Hepatocellular carcinoma (HCC) typically develops in the context of chronic liver disease, where prolonged hepatocyte exposure to inflammation drives the synergistic accumulation of genetic and epigenetic alterations. Epigenetic regulation encompasses multiple mechanisms that govern the transcription machinery accessibility to DNA. This process is regulated by the addition and removal of covalent marks on chromatin, which can either affect DNA-histone interactions or serve as scaffolds for other proteins, among other mechanisms. Recent research has revealed that epigenetic alterations can disrupt chromatin homeostasis, redirecting transcriptional regulation to favour cancer-promoting states. Consequently, these alterations play a pivotal role in the acquisition of cancer hallmarks and provide insights into several biological processes involved in hepatocarcinogenesis. This review highlights the key epigenetic mechanisms underlying the development, progression and dissemination of HCC, with a particular focus on DNA methylation and histone post-translational modifications. This knowledge is relevant for guiding the development of innovative therapeutic approaches based on epigenetic modulators.

Approximately 97% of the human genome comprises noncoding sequences, with nearly half originating from transposable elements. Among these, retrotransposons represent a critical subclass that replicates via a "copy-and-paste" mechanism and significantly influences the regulation of host genomes. In both normal and pathologic contexts, retrotransposons contribute to a vast reservoir of regulatory elements that can modulate the expression of genes. If left unchecked, retrotransposons can substantially affect host transcriptional programs and genomic integrity. Therefore, various mechanisms, including epigenetic modifications, have been employed to mitigate their potentially deleterious effects. In diseases such as cancer, the epigenome is often significantly reprogrammed, which can lead to retrotransposon dysregulation. Drawing insights from recent studies conducted in human and murine cells, this review examines how retrotransposons expand the complexity of mammalian genomes, describes the impact of their epigenetic dysregulation on cancer development, and highlights the potential of targeting these sequences for therapeutic strategies.

Emerging evidence emphasizes the critical role of alternative polyadenylation (APA) in posttranscriptional regulation of genes, and APA-associated genetic variants (apaQTLs) show particular relevance for multiple disease. However, genetic regulation of APA and its role in non-small cell lung cancer (NSCLC) risk have not been thoroughly studied. Here, by leveraging genotype and APA data from The Cancer Genome Atlas, the association between genetic variation and APA is determined in NSCLC samples. The identified apaQTLs are distinct from eQTLs and are preferentially enriched in functionally relevant characteristics, including poly(A) motifs, APA-associated RBP binding sites, functional elements, and known NSCLC risk loci. Moreover, genes associated with apaQTLs are broadly involved in cancer-related biological process. Of note, integration of apaQTL variants with traditional GWAS-derived PRS is proved as a potential screening tool for NSCLC. By integrating large-scale population and biological experiments, a functional apaQTL variant rs9606 in LYRM4 is identified. Mechanistically, rs9606 induces aberrant APA process of LYRM4 via allele-specific interacting with NUDT21, which lead to increased expression of oncogene LYRM4 and thus contribute to NSCLC risk. This study demonstrates the distinct contribution of APA-associated genetic variants in NSCLC risk, providing critical clues and potential targets for NSCLC etiology and clinical intervention.

The global population's aging and growth will likely result in an increase in chronic aging-related diseases. Early diagnosis could improve the medical care and quality of life. Many diseases are linked to misfolding or conformational changes in biomarker peptides and proteins, which affect their function and binding properties. Current clinical methods struggle to detect and quantify these changes. Therefore, there is a need for sensitive conformational sensors that can detect low-concentration analytes in biofluids. Nanopore electrical detection has shown potential in sensing subtle protein and peptide conformation changes. This technique can detect single molecules label-free while distinguishing shape or physicochemical property changes. Its proven sensitivity makes nanopore sensing technology promising for ultra-sensitive, personalized point-of-care devices. We focus on the capability of nanopore sensing for detecting and quantifying conformational modifications and enantiomers in biomarker proteins and peptides and discuss this technology as a solution to future societal health challenges.

The treatment of metastatic melanoma has long posed a complex challenge within clinical practice. Previous studies have found that EMT transcription factors are essential in the development of various cancers through their induction of EMT. Here, we demonstrate that Snail2 expression is dramatically increased in melanoma and is associated with an adverse prognosis. Elevated Snail2 in melanoma cells enhanced migratory and invasive capabilities in vitro and in vivo. Furthermore, RNA-Seq analysis revealed a significant reduction of IGFBP3 expression in melanoma cells overexpressing Snail2. IGFBP3 might mitigate the Snail2's ability to promote melanoma metastasis via the PI3K-AKT pathway. Moreover, Snail2 and HDAC3 collaborate to suppress IGFBP3 transcription through H3K4 deacetylation and H4K5 delactylation. Additionally, the combination of HDAC3 and p-GSK-3β inhibitors significantly improved the treatment outcomes for lung metastasis in melanoma in vivo. The results of our study indicate that Snail2, HDAC3, and IGFBP3 play significant roles in melanoma progression and represent promising therapeutic targets.

PJA2 is documented to degrade various substrates. Nevertheless, the role of PJA2 as an E3 ubiquitin-protein ligase in colorectal cancer (CRC) progression remains unexplored. The correlation between PJA2 mRNA levels and clinical characteristics is investigated using data from The Cancer Genome Atlas (TCGA) database. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) are utilized to evaluate PJA2 expression levels in CRC tissues. The biological functions of PJA2 are confirmed through colony formation assays and azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model of CRC, among other experimental approaches. The underlying molecular mechanisms of PJA2 action are elucidated using RNA sequencing (RNA-seq), co-immunoprecipitation (co-IP), proximity ligation assay (PLA), and chromatin immunoprecipitation (ChIP). Our research discovered that PJA2 is downregulated in CRC tissues and decreased PJA2 expression correlates with poor prognosis. Functionally, in vivo and in vitro experiments uncovered that PJA2 inhibits tumor cell proliferation and promotes apoptosis. Mechanistically, PJA2 recognized histone deacetylase 2 (HDAC2) via its RING-B-box domain (RBD) and bind to the N-terminal of HDAC2, facilitating ubiquitination at the lysine 90 (K90) residue. PJA2-mediated degradation of HDAC2 counteracts the transcriptional repression of the interferon-induced protein with the tetratricopeptide repeats (IFIT) family, thereby suppressing CRC progression. The data demonstrates that PJA2 suppresses CRC progression through the PJA2/HDAC2/IFIT axis, and its expression is regulated by HDAC2, thus constituting a positive feedback loop. Consequently, PJA2 may serve as a potential therapeutic target for CRC, and interrupting this feedback loop can represent a viable treatment strategy to restrain CRC progression.

Glioblastoma (GBM) is the most lethal primary brain tumor with intra-tumoral hierarchy of glioblastoma stem cells (GSCs). The heterogeneity of GSCs within GBM inevitably leads to treatment resistance and tumor recurrence. Molecular mechanisms of different cellular state GSCs remain unclear. Here, we find that classical (CL) and mesenchymal (MES) GSCs are enriched in reactive immune region and high CL-MES signature informs poor prognosis in GBM. Through integrated analyses of GSCs RNA sequencing and single-cell RNA sequencing datasets, we identify specific GSCs targets, including MEOX2 for the CL GSCs and SRGN for the MES GSCs. MEOX2-NOTCH and SRGN-NFκB axes play important roles in promoting proliferation and maintaining stemness and subtype signatures of CL and MES GSCs, respectively. In the tumor microenvironment, MEOX2 and SRGN mediate the resistance of CL and MES GSCs to macrophage phagocytosis. Using genetic and pharmacologic approaches, we identify FDA-approved drugs targeting MEOX2 and SRGN. Combined CL and MES GSCs targeting demonstrates enhanced efficacy, both in vitro and in vivo. Our results highlighted a therapeutic strategy for the elimination of heterogeneous GSCs populations through combinatorial targeting of MEOX2 and SRGN in GSCs.

Post-translational modifications (PTMs) on histones play a crucial role in determining the structure and function of chromatin, thereby regulating the eukaryotic gene expression. Histone lysine methylation and acetylation are among the most widespread and biomedically important PTMs, with new chemical tools for their examination in high demand. Here, we report the first use of γ-selenalysine as an efficient lysine mimic for enzymatic methylation, acetylation, and deacetylation reactions catalyzed by histone lysine methyltransferases, acetyltransferases, and a deacetylase. We also show that easily accessible selenocysteine and cysteine residues can undergo chemo- and site-selective alkylation reactions to generate both unmodified and modified γ-selenalysine and related γ-thialysine residues in histone peptides. This dual-modification strategy enables the site-specific incorporation of two distinct functionalities into peptides, mimicking lysine post-translational modifications commonly found on histones. Our research presents a novel approach in which selenocysteine serves as a unique handle for the chemoselective introduction of selenalysine, along with its methylated and acetylated analogues. These tools are designed to facilitate the study of epigenetic proteins that are important for human health and disease.

In recent years, abiotic stresses, including droughts, floods, high temperatures, and salinity, have become increasingly frequent and severe. These stresses significantly hinder crop yields and product quality, posing substantial challenges to sustainable agriculture and global food security. Simultaneously, the rapidly growing global population exacerbates the need to enhance crop production under worsening environmental conditions. Consequently, the development of effective strategies to strengthen the resilience of crop plants against high temperatures, water scarcity, and extreme environmental conditions is critical for mitigating the impacts of abiotic stress. Plants respond to these environmental challenges by reprogramming their transcriptome and metabolome. Common strategies for developing stress-tolerant plants include screening germplasm, generating transgenic crop plants, and employing genome editing techniques. Recently, chemical treatment has emerged as a promising approach to enhance abiotic stress tolerance in crops. This technique involves the application of exogenous chemical compounds that induce molecular and physiological changes, thereby providing a protective shield against abiotic stress. Forward and reverse genetic approaches have facilitated the identification of chemicals capable of modulating plant responses to abiotic stresses. These priming agents function as epigenetic regulators, agonists, or antagonists, playing essential roles in regulating stomatal closure to conserve water, managing cellular signaling through reactive oxygen species and metabolites to sustain plant growth, and activating gluconeogenesis to enhance cellular metabolism. This review summarizes recent advancements in the field of chemical priming and explores strategies to improve stress tolerance and crop productivity, thereby contributing to the enhancement of global food security.

Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, patients inevitably develop acquired drug resistance, resulting in recurrence or metastasis. It is important to identify novel effective therapeutic targets to reverse acquired TKI resistance.

Bioinformatics analysis revealed that nicotinamide N-methyltransferase (NNMT) was upregulated in EGFR-TKI resistant cells and tissues via EGR1-mediated transcriptional activation. High NNMT levels were correlated with poor prognosis in EGFR-mutated NSCLC patients, which could promote resistance to EGFR-TKIs in vitro and in vivo. Mechanistically, NNMT catalyzed the conversion of nicotinamide to 1-methyl nicotinamide by depleting S-adenosyl methionine (the methyl group donor), leading to a reduction in H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) and subsequent epigenetic activation of EGR1 and ALDH3A1. In addition, ALDH3A1 activation increased lactic acid levels, which further promoted NNMT expression via p300-mediated histone H3K18 lactylation on its promoter. Thus, NNMT mediates the formation of a double positive feedback loop via EGR1 and lactate, EGR1/NNMT/EGR1 and NNMT/ALDH3A1/lactate/NNMT. Moreover, the combination of a small-molecule inhibitor for NNMT (NNMTi) and osimertinib exhibited promising potential for the treatment of TKI resistance in an NSCLC osimertinib-resistant xenograft model.

The combined contribution of these two positive feedback loops promotes EGFR-TKI resistance in NSCLC. Our findings provide new insight into the role of histone methylation and histone lactylation in TKI resistance. The pivotal NNMT-mediated positive feedback loop may serve as a powerful therapeutic target for overcoming EGFR-TKI resistance in NSCLC.

Omega-3 (n - 3) and omega-6 (n - 6) polyunsaturated fatty acids (PUFAs) are vital for human health, but an imbalance between these types is associated with chronic diseases, including cancer. Alpha-linolenic acid (ALA), a n - 3 PUFA, shows promise as an anticancer agent in both laboratory and animal studies. However, the precise molecular mechanisms underlying ALA's actions against cancer-related epigenetic modifiers (CaEpM) remain unclear. To understand this, we employed network pharmacology (NP) and molecular docking techniques. Our study identified 51 potential ALA targets and GO and KEGG pathway analysis revealed possible molecular targets and signaling pathways of ALA against CaEpM. From PPI analysis, EZH2, KAT2B, SIRT1, KAT2A, KDM6B, EHMT2, WDR5, SETD7, SIRT2, and HDAC3 emerged as the top 10 potential targets. Additionally, GeneMANIA functional association (GMFA) network analysis of these top 10 targets was performed to enhance NP insights and explore ALA's multi-target approach. After an exhaustive analysis of the core FGN subnetwork, it became evident that 9 out of the 15 targets-namely EZH2, SUZ12, EED, PARP1, HDAC3, DNMT1, NCOR2, KAT2B, and TRRAP-manifested evidently strong and abundant interconnections among each other. Molecular docking of both top 10 targets and core FGN targets confirmed strong binding affinity between ALA and SIRT2, WDR5, KDM6B, EHMT2, HDAC3, EZH2, PARP1, and KAT2B, underscoring their roles in ALA's anti-CaEpM mechanism. Our findings suggest that ALA may target key signaling pathways related to transcriptional regulation, microRNA involvement, stem cell pluripotency and cellular senescence in cancer epigenetics. These findings illuminate ALA's potential as a multi-target agent against CaEpM.Communicated by Ramaswamy H. Sarma.

To understand the complex relationship between histone mark activity and gene expression, recent advances have used in silico predictions based on large-scale machine learning models. However, these approaches have omitted key contributing factors like cell state, histone mark function or distal effects, which impact the relationship, limiting their findings. Moreover, downstream use of these models for new biological insight is lacking. Here, we present the most comprehensive study of this relationship to date - investigating seven histone marks in eleven cell types across a diverse range of cell states. We used convolutional and attention-based models to predict transcription from histone mark activity at promoters and distal regulatory elements. Our work shows that histone mark function, genomic distance and cellular states collectively influence a histone mark's relationship with transcription. We found that no individual histone mark is consistently the strongest predictor of gene expression across all genomic and cellular contexts. This highlights the need to consider all three factors when determining the effect of histone mark activity on transcriptional state. Furthermore, we conducted in silico histone mark perturbation assays, uncovering functional and disease related loci and highlighting frameworks for the use of chromatin deep learning models to uncover new biological insight.

Preeclampsia is a major challenge for obstetricians due to its severe impacts on maternal and fetal health. Lysine lactylation (Kla) derived from lactate is a novel type of post-translational modification which has been confirmed to affect the malignant progression of diseases as an epigenetic modifier. However, the systemic lactylome profiling of preeclampsia is still unclear.

Immunohistochemistry and protein immunoassay were performed on placenta tissues from preeclamptic patients and control pregnancies to compare lactylation levels between the groups. Then liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized for quantitative lactylomic analysis and proteomic assessment for proteins with differentially lactated modification. Bioinformatics analyses were applied to reveal the conserved motif sequences and enrichment pathways.

Significant differences in protein lactylation levels were evident in the placenta between preeclamptic and control groups, with modifications observed in both histone and non-histone proteins. Lactylome analysis showed significant downregulation of 59 Kla proteins and 69 Kla sites in preeclamptic placentas, whereas 44 proteins and 60 sites were upregulated. These differentially lactylated proteins were primarily mitochondrial and associated with the citrate cycle (TCA cycle). Enriched metabolic pathways linked to lactylation included those important for vascular muscle contraction, platelet activation, and several signaling pathways like PI3K-Akt, PPAR, and cholesterol metabolism.

Preeclamptic placentas exhibit distinct lactylation profiles compared to normal pregnancies, primarily affecting mitochondrial and TCA cycle-related energy metabolism. These changes contribute to the pathophysiology of preeclampsia by involving metabolic pathways critical for angiogenesis and endothelial function.

Condensin, a family of structural maintenance of chromosome complexes, has been shown to regulate chromosome compaction and segregation during mitosis. NCAPD3, a HEAT-repeat subunit of condensin II, plays a dominant role in condensin-mediated chromosome dynamics but remains unexplored in lymphoma.

The study aims to unravel the molecular function and mechanism of NCAPD3 in diffuse large B-cell lymphoma (DLBCL).

The expression and clinical significance of NCAPD3 were assessed in public database and clinical specimens. Chromosome spreads, co-immunoprecipitation (co-IP), mass spectrometry (MS), and chromatin immunoprecipitation (ChIP) assays were conducted to untangle the role and mechanism of NCAPD3 in DLBCL.

NCAPD3 was highly expressed in DLBCL, correlated with poor prognosis. NCAPD3 deficiency impeded cell proliferation, induced apoptosis and increased the chemosensitivity. Instead, NCAPD3 overexpression facilitated cell proliferation. In vivo experiments further indicated targeting NCAPD3 suppressed tumor growth. Noteworthily, NCAPD3 deficiency disturbed the mitosis, triggering the formation of aneuploids. To reveal the function of NCAPD3 in DLBCL, chromosome spreads were conducted, presenting that chromosomes became compact upon NCAPD3 overexpression, instead, loose, twisted and lacking axial rigidity upon NCAPD3 absence. Meanwhile, the classical transcription-activated marker, H3K4 trimethylation, was found globally upregulated after NCAPD3 knockout, suggesting that NCAPD3 might participate in chromatin remodeling and transcription regulation. MS revealed NCAPD3 could interact with transcription factor, TFII I. Further co-IP and ChIP assays verified NCAPD3 could be anchored at the promoter of SIRT1 by TFII I and then supported the transcription of SIRT1 via recognizing H3K9 monomethylation (H3K9me1) on SIRT1 promoter. Function reversion assay verified the oncogenic role of NCAPD3 in DLBCL was partially mediated by SIRT1.

This study demonstrated that dysregulation of NCAPD3 could disturb chromosome compaction and segregation and regulate the transcription activity of SIRT1 in an H3K9me1-dependent manner, which provided novel insights into targeted strategy for DLBCL.

Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a subtype associated with poor survival outcomes. Despite identifying therapeutic targets through molecular characterization, targeted therapies have limited success. New strategies using immune-competent tissue models are needed to understand how DLBCL cells evade treatment. Here, synthetic hydrogel-based lymphoma organoids are used to demonstrate how signals in the lymphoid tumor microenvironment (Ly-TME) can alter B cell receptor (BCR) signaling and specific histone modifications, tri-methylation of histone 3 at lysine 9 (H3K9me3), dampening the effects of BCR pathway inhibition. Using imaging modalities, T cells increase DNA methyltransferase 3A expression and cytoskeleton formation in proximal ABC-DLBCL cells, regulated by H3K9me3. Expansion microscopy on lymphoma organoids reveals T cells increase the size and quantity of segregated H3K9me3 clusters in ABC-DLBCL cells. Findings suggest the re-organization of higher-order chromatin structures that may contribute to evasion or resistance to therapy via the emergence of novel transcriptional states. Treating ABC-DLBCL cells with a G9α histone methyltransferase inhibitor reverses T cell-mediated modulation of H3K9me3 and overcomes T cell-mediated attenuation of treatment response to BCR pathway inhibition. This study emphasizes the Ly-TME's role in altering DLBCL fate and suggests targeting aberrant signaling and microenvironmental cross-talk that can benefit high-risk patients.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Hepatitis B virus (HBV) is the main pathogen for HCC development. HBV covalently closed circular DNA (cccDNA) forms extra-host chromatin-like minichromosomes in the nucleus of hepatocytes with host histones, non-histones, HBV X protein (HBx) and HBV core protein (HBc). Epigenetic alterations are dynamic and reversible, which regulate gene expression without altering the DNA sequence and play a pivotal role in the regulation of HCC onset and progression. The aim of this review is to elucidate the deregulation of epigenetic mechanisms involved in the pathogenesis of HBV-related HCC (HBV-HCC), including post-translational histone and non-histone modifications, DNA hypermethylation and hypomethylation, non-coding RNA modification on HBV cccDNA minichromosomes and host factors, effecting the replication/transcription of HBV cccDNA and transcription/translation of host genes, and thus HBV-HCC progression. It is expected that the epigenetic regulation perspective provides new ways for more in-depth development of therapeutic control of HBV-HCC.

Congenital anomalies of the kidney and urinary tract (CAKUT) represent a major health burden in humans. Phenotypes range from renal hypoplasia or renal agenesis, cystic renal dysplasia, duplicated or horseshoe kidneys to obstruction of the ureteropelvic junction, megaureters, duplicated ureters, urethral valves or bladder malformations. Over the past decade, next-generation sequencing has identified numerous causative genes; however, the genetic basis of most cases remains unexplained. It is assumed that environmental factors have a significant impact on the phenotype, but, overall, the pathogenesis has remained poorly understood. Interestingly however, CAKUT is a common phenotypic feature in two human syndromes, Kabuki and Koolen-de Vries syndrome, caused by dysfunction of genes encoding for KMT2D and KANSL1, both members of protein complexes playing an important role in histone modifications. In this chapter, we discuss current knowledge regarding epigenetic modulation in renal development and a putatively under-recognized role of epigenetics in CAKUT.

Post-translational modifications (PTMs) of proteins dynamically build the buffering and adapting interface between oncogenic mutations and environmental stressors, on the one hand, and cancer cell structure, functioning, and behavior. Aberrant PTMs can be considered as enabling characteristics of cancer as long as they orchestrate all malignant modifications and variability in the proteome of cancer cells, cancer-associated cells, and tumor microenvironment (TME). On the other hand, PTMs of proteins can enhance anticancer mechanisms in the tumoral ecosystem or sustain the beneficial effects of oncologic therapies through degradation or inactivation of carcinogenic proteins or/and activation of tumor-suppressor proteins. In this review, we summarized and analyzed a wide spectrum of PTMs of proteins involved in all regulatory mechanisms that drive tumorigenesis, genetic instability, epigenetic reprogramming, all events of the metastatic cascade, cytoskeleton and extracellular matrix (ECM) remodeling, angiogenesis, immune response, tumor-associated microbiome, and metabolism rewiring as the most important hallmarks of cancer. All cancer hallmarks develop due to PTMs of proteins, which modulate gene transcription, intracellular and extracellular signaling, protein size, activity, stability and localization, trafficking, secretion, intracellular protein degradation or half-life, and protein-protein interactions (PPIs). PTMs associated with cancer can be exploited to better understand the underlying molecular mechanisms of this heterogeneous and chameleonic disease, find new biomarkers of cancer progression and prognosis, personalize oncotherapies, and discover new targets for drug development.

Significance: Growing evidence indicates the importance of redox reactions homeostasis, mediated predominantly by reactive oxygen species (ROS) in influencing the development, differentiation, progression, metastasis, programmed cell death, tumor microenvironment, and therapeutic resistance of cancer. Therefore, reviewing the ROS-linked epigenetic changes in cancer is fundamental to understanding the progression and prevention of cancer. Recent Advances: We review in depth the molecular mechanisms involved in ROS-mediated epigenetic changes that lead to alteration of gene expression by altering DNA, modifying histones, and remodeling chromatin and noncoding RNA. Critical Issues: In cancerous cells, alterations of the gene-expression regulatory elements could be generated by the virtue of imbalance in tumor microenvironment. Various oxidizing agents and mitochondrial electron transport chain are the major pathways that generate ROS. ROS plays a key role in carcinogenesis by activating pro-inflammatory signaling pathways and DNA damage. This loss of ROS-mediated epigenetic regulation of the signaling pathways may promote tumorigenesis. We address all such aspects in this review. Future Directions: Developments in this growing field of epigenetics are expected to contribute to further our understanding of human health and diseases such as cancer and to test the clinical applications of redox-based therapy. Recent studies of the cancer-epigenetic landscape have revealed pervasive deregulation of the epigenetic factors in cancer. Thus, the study of interaction between ROS and epigenetic factors in cancer holds a great promise in the development of effective and targeted treatment modalities. Antioxid. Redox Signal. 00, 000-000.

The "epigenetics" concept was first described in 1942. Thus far, chemical modifications on histones, DNA, and RNA have emerged as three important building blocks of epigenetic modifications. Many epigenetic modifications have been intensively studied and found to be involved in most essential biological processes as well as human diseases, including cancer. Precisely and quantitatively mapping over 100 [1], 17 [2], and 160 [3] different known types of epigenetic modifications in histone, DNA, and RNA is the key to understanding the role of epigenetic modifications in gene regulation in diverse biological processes. With the rapid development of sequencing technologies, scientists are able to detect specific epigenetic modifications with various quantitative, high-resolution, whole-genome/transcriptome approaches. Here, we summarize recent advances in epigenetic modification sequencing technologies, focusing on major histone, DNA, and RNA modifications in mammalian cells.

Urothelial carcinoma (UC) is the most common histological subtype of bladder tumors; however, bladder cancer represents a heterogeneous group of diseases with at least 40 distinct histological subtypes. Among these, the 2022 World Health Organization classification of urinary tract tumors identifies a range of less common subtypes of invasive UC, formerly known as variants, which are considered high-grade tumors, including squamous cell, small-cell, sarcomatoid urothelial, micropapillary, plasmacytoid, and urachal carcinomas, and adenocarcinoma. Their accurate histological diagnosis is critical for risk stratification and therapeutic decision-making, as most subtype histologies are associated with poorer outcomes than conventional UC. Despite the importance of a precise diagnosis, high-quality evidence on optimal treatments for subtype histologies remains limited owing to their rarity. In particular, neoadjuvant and adjuvant chemotherapy have not been well characterized, and prospective data are scarce. For advanced-stage diseases, clinical trial participation is strongly recommended to address the lack of robust evidence. Advances in molecular pathology and the development of targeted therapies and immunotherapies have reshaped our understanding and classification of bladder cancer subtypes, spurring efforts to identify predictive biomarkers to guide personalized treatment strategies. Nevertheless, the management of rare bladder cancer subgroups remains challenging because they are frequently excluded from clinical trials. For localized disease, curative options such as surgical resection or radiotherapy are available; however, treatment options become more limited in recurrence or metastasis, where systemic therapy is primarily used to control disease progression and palliate symptoms. Herein, we present recent advances in the management of urothelial and non-urothelial bladder cancer subtypes and also explore the current evidence guiding their treatment and emphasize the challenges and perspectives of future therapeutic strategies.

Genetic mutations arising from various internal and external factors drive cells to become cancerous. Cancerous cells undergo numerous changes, including metabolic reprogramming and epigenetic modifications, to support their abnormal proliferation. This metabolic reprogramming leads to the altered expression of many metabolic enzymes and the accumulation of metabolites. Recent studies have shown that these enzymes and metabolites can serve as substrates or cofactors for chromatin-modifying enzymes, thereby participating in epigenetic modifications and promoting carcinogenesis. Additionally, epigenetic modifications play a role in the metabolic reprogramming and immune evasion of cancer cells, influencing cancer progression. This review focuses on the origins of cancer, particularly the metabolic reprogramming of cancer cells and changes in epigenetic modifications. We discuss how metabolites in cancer cells contribute to epigenetic remodeling, including lactylation, acetylation, succinylation, and crotonylation. Finally, we review the impact of epigenetic modifications on tumor immunity and the latest advancements in cancer therapies targeting these modifications.

In the nucleus, the VRK1 Ser-Thr kinase is distributed in nucleoplasm and chromatin, where it has different roles. VRK1 expression increases in response to mitogenic signals. VRK1 regulates cyclin D1 expression at G0 exit and facilitates chromosome condensation at the end of G2 and G2/M progression to mitosis. These effects are mediated by the phosphorylation of histone H3 at Thr3 by VRK1, and later in mitosis by haspin. VRK1 regulates the apigenetic patterns of histones in processes requiring chromating remodeling, such as transcription, replication and DNA repair. VRK1 is overexpressed in tumors, facilitating tumor progression and resistance to genotoxic treatments. VRK1 also regulates the organization of Cajal bodies assembled on coilin, which are necessary for the assembly of different types of RNP complexes. VRK1 pathogenic variants cuase defects in Cajal bodies, functionally altering neurons with long axons and leading to neurological diseases, such as amyotrophic laterla sclerosis, spinal muscular atrophy, distal hereditay motor neuropathies and Charcot-Marie-Tooth.

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of epigenome, modulating gene expression through DNA methylation, histone modification, and/or chromosome remodeling. Dysregulated lncRNAs act as oncogenes or tumor suppressors, driving tumor progression by shaping the cancer epigenome. By interacting with the writers, readers, and erasers of the epigenetic script, lncRNAs induce epigenetic modifications that bring about changes in cancer cell proliferation, apoptosis, epithelial-mesenchymal transition, migration, invasion, metastasis, cancer stemness and chemoresistance. This review analyzes and discusses the multifaceted role of lncRNAs in cancer pathobiology, from cancer genesis and progression through metastasis and therapy resistance. It also explores the therapeutic potential of targeting lncRNAs through innovative diagnostic, prognostic, and therapeutic strategies. Understanding the dynamic interplay between lncRNAs and epigenome is crucial for developing personalized therapeutic strategies, offering new avenues for precision cancer medicine.

Histones are essential nuclear proteins that package eukaryotic DNA into chromosomes, play a vital role in gene regulation, DNA replication, DNA repair and chromosome condensation. Understanding histone modifications is crucial for grasping biological and disease-related processes. Specific alterations in histone modifications serve as sensitive and selective biomarkers for conditions like cancer, impacting both tumor and immune cells and affecting their interactions. Indeed, the interest in histone modifications is growing in the field of tumor immunology and immunotherapy. Different techniques have been developed to characterize histone proteins and their modifications. Here, we present a simple acid extraction protocol to identify and quantify histones. The workflow described here can be used to detect and measure histone proteins or specific residues of histone, even capturing changes resulting from treatment with epigenetic drugs (Epi-drugs) or other drugs in in different human cancer cell line models.

In the era of transcriptomics, the role of epigenetics in the study of cancers in females has gained increasing recognition. This article explores the impact of epigenetic modifications, such as DNA methylation, histone modification, and non-coding RNA, on cancers in females, including breast, cervical, and ovarian cancers (1). Our findings suggest that these epigenetic markers not only influence tumor onset, progression, and metastasis but also present novel targets for therapeutic intervention. Detailed analyses of DNA methylation patterns have revealed aberrant events in cancer cells, particularly promoter region hypermethylation, which may lead to silencing of tumor suppressor genes. Furthermore, we examined the complex roles of histone modifications and long non-coding RNAs in regulating the expression of cancer-related genes, thereby providing a scientific basis for developing targeted epigenetic therapies. Our research emphasizes the importance of understanding the functions and mechanisms of epigenetics in cancers in females to develop effective treatment strategies. Future therapeutic approaches may include drugs targeting specific epigenetic markers, which could not only improve therapeutic outcomes but also enhance patient survival and quality of life. Through these efforts, we aim to offer new perspectives and hope for the prevention, diagnosis, and treatment of cancers in females.

Precise regulation of gene expression is crucial to development. Enhancers, the core of gene regulation, determine the spatiotemporal pattern of gene transcription. Since many disease-associated mutations are characterized in enhancers, the research on enhancer will provide clues to precise medicine. Rapid advances in high-throughput sequencing technology facilitate the characterization of enhancers at genome wide, but understanding the functional mechanisms of enhancers remains challenging. Herein, we provide a panorama of enhancer characteristics, including epigenetic modifications, enhancer transcripts, and enhancer-promoter interaction patterns. Furthermore, we outline the applications of high-throughput sequencing technology and functional genomics methods in enhancer research. Finally, we discuss the role of enhancers in human disease and their potential as targets for disease prevention and treatment strategies.

Loss of expression of tumour suppressor PAX2 and MMR deficiency (dMMR) has been frequently seen in endometrial endometrioid adenocarcinoma (EEC). However, the relationship between PAX2 expression and MMR status is unknown.

We studied the PAX2 expression and examined its association with MMR status at the protein and genetic levels in 180 cases of EEC. Overall, total loss of PAX2 expression was found in about 70%, while retained PAX2 expression was seen in 30% of EEC. Among 125 cases with loss of PAX2, 68.8% were found in EECs with pMMR, while 31.2% were seen in those with dMMR. Among 55 cases of EECs with retained PAX2 expression, 92.7% were EECs with dMMR and 7.3% were those with pMMR (P < 0.001). While dMMR cases with MLH1 hypermethylation show almost equal retained or loss of PAX2 expression (52% versus 48%), dMMR with genetic alterations had significantly more retained PAX2 expression than loss of PAX2 (92.3% versus 7.7%), regardless of somatic or germline mutations. Loss of PAX2 was observed in 97.3% of dMMR with MLH1 hypermethylation compared to 2.7% of dMMR with genetic alterations (P < 0.001). Aggressive features such as higher tumour grades (FIGO 2-3) and advanced clinical stage (T2-T4) were significantly more frequently seen in dMMR with retained PAX2 expression, compared those to pMMR with loss of PAX2 expression.

Our study demonstrates a close correlation between retained PAX2 expression and dMMR in EEC. The molecular mechanism and clinical significance linking these two pathways in EEC remains to be unravelled.

Among cancer-related deaths worldwide, colorectal cancer ranks second, accounting for 1.2% of deaths in those under 50 years and 0.6% of deaths in those between 50 and 54 years. The anticancer drug 5-fluorouracil is widely used to treat colorectal cancer. Due to a better understanding of the drug's mechanism of action, its anticancer activity has been increased through a variety of therapeutic alternatives. Clinical use of 5-FU has been severely restricted due to drug resistance. The chemoresistance mechanism of 5-FU is challenging to overcome because of the existence of several drug efflux transporters, DNA repair enzymes, signaling cascades, classical cellular processes, cancer stem cells, metastasis, and angiogenesis. Curcumin, a potent phytocompound derived from Curcuma longa, functions as a nuclear factor (NF)-κB inhibitor and sensitizer to numerous chemotherapeutic drugs. Piperine, an alkaloid found in Piper longum, inhibits cancer cell growth, causing cell cycle arrest and apoptosis. This review explores the mechanism of 5-FU-induced chemoresistance in colon cancer cells and the role of curcumin and piperine in enhancing the sensitivity of 5-FU-based chemotherapy. CLINICAL TRIAL REGISTRATION: Not applicable.

The purpose of this article is to provide a literature review of the epigenetic understanding of conjunctival melanoma (CM), with a primary focus on current gaps in knowledge and future directions in research. CM is a rare aggressive cancer that predominantly affects older adults. Local recurrences and distant metastases commonly occur in CM patients; however, their prediction and management remain challenging. Hence, there is currently an unmet need for useful biomarkers and more effective treatments to improve the clinical outcomes of these patients. Like other cancers, CM occurrence and prognosis are believed to be influenced by multiple genetic and epigenetic factors that contribute to tumor development/progression/recurrence/spread, immune evasion, and primary/acquired resistance to therapies. Epigenetic alterations may involve changes in chromatin conformation/accessibility, post-translational histone modifications or the use of histone variants, changes in DNA methylation, alterations in levels/functions of short (small) or long non-coding RNAs (ncRNAs), or RNA modifications. While recent years have witnessed a rapid increase in available epigenetic technologies and epigenetic modulation-based treatment options, which has enabled the development/implementation of various epi-drugs in the cancer field, the epigenetic understanding of CM remains limited due to a relatively small number of epigenetic studies published to date. These studies primarily investigated DNA methylation, ncRNA (e.g., miRNA or circRNA) expression, or RNA methylation. While these initial epigenetic investigations have revealed some potential biomarkers and/or therapeutic targets, they had various limitations, and their findings warrant replication in independent and larger studies/samples. In summary, an in-depth understanding of CM epigenetics remains largely incomplete but essential for advancing our molecular knowledge and improving clinical management/outcomes of this aggressive disease.

Cancer has arisen from both genetic mutations and epigenetic changes, making epigenetics a crucial area of research for innovative cancer prevention and treatment strategies. This dual perspective has propelled epigenetics into the forefront of cancer research. This review highlights the important roles of DNA methylation, histone modifications and non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs, which are key regulators of cancer-related gene expression. It explores the potential of epigenetic-based therapies to revolutionize patient outcomes by selectively modulating specific epigenetic markers involved in tumorigenesis. The review examines promising epigenetic biomarkers for early cancer detection and prognosis. It also highlights recent progress in oligonucleotide-based therapies, including antisense oligonucleotides (ASOs) and antimiRs, to precisely modulate epigenetic processes. Furthermore, the concept of epigenetic editing is discussed, providing insight into the future role of precision medicine for cancer patients. The integration of nanomedicine into cancer therapy has been explored and offers innovative approaches to improve therapeutic efficacy. This comprehensive review of recent advances in epigenetic-based cancer therapy seeks to advance the field of precision oncology, ultimately culminating in improved patient outcomes in the fight against cancer.

As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation and the enzyme complexes represent a major frontier for therapeutic development. Clinically viable therapies targeting the activities of histone lysine methyltransferases (HKMT) and demethylases (HKDMs) have only recently begun to emerge following FDA approval of the EZH2 inhibitor tazemetostat in 2020 and remain limited to compounds targeting the well-studied SET domain-containing HKMTs and their opposing HKDMs. These include the H3K27 methyltransferases EZH2/EZH1, the singular H3K79 methyltransferase DOT1L, and the H3K4 methyltransferase MLL1/COMPASS as well as H3K9 and H3K36 methyltransferases. They additionally include the H3K4/9-preferential demethylase LSD1 and the H3K4-, H3K27-, and H3K36-preferential KDM5, KDM6, and KDM2 demethylase subfamilies, respectively. This Review discusses the results of recent clinical and preclinical studies relevant to all of these existing and potential therapies. It provides an update on advancements in therapeutic development, as well as more basic molecular understanding, within the past 5 years approximately. It also offers a perspective on histone lysine methylation that departs from the long-predominant "histone code" metaphor, emphasizing complex-disrupting inhibitors and proximity-based approaches rather than catalytic domain inhibitors in the outlook for future therapeutic development.

Cancer cells undergo metabolic reprogramming that is intricately linked to malignancy. Protein acylations are especially responsive to metabolic changes, influencing signal transduction pathways and fostering cell proliferation. However, as a novel type of acylations, the involvement of malonylation in cancer remains poorly understood. In this study, we observed a significant reduction in malonyl-CoA levels in hepatocellular carcinoma (HCC), which correlated with a global decrease in malonylation. Subsequent nuclear malonylome analysis unveiled nucleolin (NCL) malonylation, which was notably enhanced in HCC biopsies. we demonstrated that NCL undergoes malonylation at lysine residues 124 and 398. This modification triggers the translocation of NCL from the nucleolus to nucleoplasm and cytoplasm, binding to AKT mRNA, and promoting AKT translation in HCC. Silencing AKT expression markedly attenuated HCC cell proliferation driven by NCL malonylation. These findings collectively highlight nuclear signaling in modulating AKT expression, suggesting NCL malonylation as a novel mechanism through which cancer cells drive cell proliferation.