Clinical Epigenetics最新文献

Background: Histone deacetylases (HDACs) are central epigenetic regulators in non-small cell lung cancer (NSCLC), yet responses to HDAC inhibitors (HDACi) vary markedly between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). We asked how the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) rewires lineage-specific transcriptional programs and whether SAHA-aligned modules of genes, rather than individual loci, capture clinically relevant vulnerabilities in each subtype.

Methods: LUAD-like NCI-H1299 (TP53^del, NRAS^Q61K) and LUSC-like NCI-H1703 (TP53^WT, PDGFRA^amp, PIK3CA^E542K) cells were treated with SAHA (10 µM, 24 h) or DMSO. Bulk RNA-seq data were analysed with edgeR (FDR < 0.05, |log₂FC|> 1), followed by GO/Reactome over-representation, Hallmark GSEA, and STRING-based protein-protein interaction mapping. We quantified apoptosis (Annexin V/PI) and motility (scratch assays under mitomycin C). SAHA "feature-sensing" modules were constructed by intersecting SAHA-responsive DEGs with overall-survival-associated genes from GEPIA2 and were scored in 592 LUAD and 551 LUSC tumours. Correlations between HDAC isoforms and module scores were used to define subtype-biased HDAC-module neighbourhoods.

Results: SAHA reprogrammed the transcriptome in both lines (1,098 DEGs in H1299; 1,532 in H1703), enforcing a shared suppression of E2F/G2-M programs but diverging in non-cell-cycle outputs. In LUAD-like H1299, SAHA upregulated morphogenesis/adhesion and KRAS_SIGNALING_DN/EMT-adjacent signatures while dampening interferon/stress pathways, and significantly reduced migration at low dose. In LUSC-like H1703, SAHA triggered a dominant cell-cycle checkpoint shutdown coupled to complement/ECM and inflammatory induction, with stronger apoptosis but only modest short-term migration restraint. Survival-anchored analysis yielded four SAHA feature-sensing modules; the LUAD_RISK module was enriched for cell-cycle/mitotic genes and was attenuated by SAHA, whereas the LUSC_RISK module captured checkpoint, ECM, and stress-response programs preferentially down-regulated in H1703. Both risk modules stratified prognosis and were linked to distinct HDAC-centred neighbourhoods (HDAC7/9-LUAD_RISK and HDAC4/6-LUSC_RISK) in TCGA tumours.

Conclusions: SAHA imposes a common anti-proliferative core but engages distinct lineage-conditioned risk modules in LUAD and LUSC-cell-cycle/migration-linked in LUAD and checkpoint/stress-linked in LUSC. These SAHA feature-sensing modules provide a mechanistic and clinically anchored framework for subtype-tailored HDAC-directed combinations and for future development of HDACi-aligned biomarkers in NSCLC.

Backgound: High-grade B-cell lymphoma with concurrent MYC and BCL2/BCL6 rearrangements (HGBL-DHL) is a highly aggressive disease that is resistant to conventional first-line immunochemotherapeutic regimens. This resistance necessitates the exploration of innovative therapeutic strategies.

Result: In this study, the combination of chidamide and selinexor showed significant synergistic antilymphoma effects in the treatment of HGBL-DHL. The synergistic effects were evidenced by the inhibition of cell proliferation, induction of apoptosis, and perturbation of the cell cycle in cell lines, as assessed by Cell Counting Kit-8, Annexin V/PI staining, and PI staining assays. Furthermore, in a xenograft mouse model of HGBL-DHL, this combination therapy markedly reduced the tumor burden without causing lethal toxicity. At the mechanistic level, the combination of chidamide and selinexor resulted in the synergistic downregulation of survivin and the PI3K/AKT signaling pathway. This dual inhibition was attributed to the interactive effects of the two drugs. The downregulation of key downstream targets of the PI3K/AKT pathway, including c-Myc, MCL1, BCL-XL, cyclin A2, and survivin, was synergistic and aligned with the phenotypic outcomes. Notably, survivin, an anti-apoptotic gene, underwent transcriptional repression by FOXO1 at the level of epigenetic regulation. Chidamide combined with selinexor synergistically down-regulated survivin in both the nucleus, cytoplasm and total protein levels via HDAC/FOXO1/survivin, HDAC3/PI3K/AKT/XPO1/survivin, XPO1/FOXO1/survivin, and XPO1/survivin axes.

Conclusion: Our preclinical data highlighted the potential synergistic efficacy of chidamide and selinexor in targeting HGBL-DHL, providing a rationale for further clinical investigation of this therapeutic combination for the treatment of this refractory disease.

Breast cancer remains a leading cause of morbidity and mortality among women worldwide, with significant heterogeneity in its development and treatment response. Recent advances in understanding the roles of the microbiome and epigenetic regulation have opened new avenues for addressing the complexities of breast cancer progression and therapeutic resistance. This review explores the intricate relationship between the gut and intratumoral microbiomes and epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAs. Specifically, we examine how microbial metabolites, particularly short-chain fatty acids (SCFAs), regulate gene expression via epigenetic mechanisms, influencing tumor growth, metastasis, and treatment response. The impact of metabolic diseases, including obesity and type 2 diabetes mellitus (T2DM), on breast cancer risk through microbiome-mediated epigenetic changes is also discussed. Furthermore, the review highlights emerging therapeutic strategies that integrate microbiome modulation with epigenetic therapies, including the use of probiotics, dietary interventions, and fecal microbiota transplantation (FMT), as well as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors. These innovative approaches hold promise for overcoming treatment resistance and improving clinical outcomes in breast cancer patients. Future research should focus on elucidating the molecular pathways through which the microbiome influences epigenetic regulation and developing personalized, microbiome-targeted therapies that enhance the efficacy of existing treatments. By targeting both the genetic and epigenetic drivers of breast cancer, microbiome-based interventions represent a novel frontier in the fight against this challenging disease.

Background: Triple-negative breast cancer (TNBC) is distinguished by high invasiveness and a tendency for recurrence. Recent studies have suggested that E3 ubiquitin ligases play a crucial role in the initiation and progression of various tumors. However, there is still an absence of systematic understanding regarding the specific function and molecular mechanisms of its member gene RNF130 in TNBC.

Methods: This study conducted a comprehensive analysis of large-scale transcriptomic data from databases such as TCGA and GEO. Additionally, single-cell RNA sequencing data from multiple breast cancer samples and their liver metastases were analyzed to evaluate the expression pattern, prognostic significance, and potential regulatory role of RNF130 in the tumor microenvironment. The effects of RNF130 on breast cancer cell proliferation, apoptosis, and chemotherapy sensitivity were explored through in vitro cell experiments and in vivo mouse models. Furthermore, the study screened and evaluated the targeted inhibitory effect of the Traditional Chinese Medicine active component Worenine on RNF130, as well as its combined therapeutic effect with paclitaxel.

Results: The findings indicated that RNF130 was notably overexpressed in breast cancer tissues and associated with unfavorable patient survival outcomes. Single-cell transcriptomic analysis revealed that RNF130 was predominantly enriched in malignant epithelial cell populations and closely associated with tumor immune evasion phenotypes. RNF130 knockdown inhibited proliferation, induced apoptosis, reduced TNF-α pathway activation, and enhanced sensitivity to paclitaxel, whereas RNF130 overexpression exerted the opposite effects. Co-culture experiments further demonstrated that RNF130 depletion promoted M1 macrophage polarization while control cells induced M2-like phenotypes. Additionally, Worenine downregulated RNF130 expression and displayed a synergistic inhibitory effect with paclitaxel.

Conclusion: This study identifies RNF130 as a critical mediator of TNBC progression that regulates tumor growth, apoptosis, immune evasion, and metabolic reprogramming, partly through activation of the TNF-α signaling pathway. Furthermore, Worenine was found to reduce RNF130 expression and enhance the antitumor effect of paclitaxel, suggesting its potential utility in combination therapy for TNBC. These findings provide mechanistic insights into RNF130-driven malignancy and offer a foundation for developing future therapeutic strategies.

Background: Histone deacetylases (HDACs) are epigenetic molecules responsible for regulation of gene transcription. Dysregulation of HDACs has been linked to neurodegenerative disease. Here, we used the class I HDAC PET radioligand [¹¹C]Martinostat to quantify and map changes in the distribution of these molecules in the brain in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In this exploratory cross-sectional study, we acquired brain PET-MR with [¹¹C]Martinostat in 14 DLB (median age 70 years (IQR 14), 21% female), 10 PD (median age 70 (8), 20% female) including four with cognitive impairment and six without, and 17 healthy control (HC) participants (median age 62 (14), 47% female). [¹¹C]Martinostat uptake was compared amongst groups using whole brain voxel-wise analysis and targeted region of interest (ROI)-based approaches, adjusted for age and sex. Regional levels were also quantified in postmortem brain bank samples.

Results: Compared to HC, [¹¹C]Martinostat uptake in DLB was increased in precentral gyrus (ROI p = 0.044) and putamen (p < 0.001), as well as in cognitive and limbic circuitry including anterior cingulate (p = 0.042) and entorhinal cortex (p = 0.023). [¹¹C]Martinostat uptake in DLB was decreased in inferior parietal cortex p < 0.001) compared to HC, consistent with prior observations in Alzheimer's disease. In PD, [¹¹C]Martinostat uptake was also increased in precentral gyrus (p = 0.013), correlating with both disease duration and Hoehn and Yahr motor stage. In postmortem DLB tissue, class I HDAC levels were elevated in anterior cingulate cortex (isoform 1 p = 0.041, isoform 3 p = 0.024) and were reduced in inferior parietal cortex (isoform 1 p < 0.001).

Conclusions: The findings of this exploratory study reveal elevated levels of class I HDACs in motor cortex in PD and bidirectional changes in their regional density in the Lewy body dementias.

Adverse childhood experiences (ACEs), such as abuse and neglect, are associated with poor health in adulthood. One proposed biological mechanism linking early adversity to health outcomes is epigenetic age acceleration (EAA), a measure of biological aging derived from DNA methylation. Understanding whether ACEs contribute to EAA might identify pathways linking early life stress to increased risk of morbidity and mortality.This systematic review and meta-analysis examined the relationship between cumulative ACE exposure and EAA in adults across 27 eligible observational studies from 1036 identified by comprehensive screening of the literature. Studies involved more female participants (median 56.6%) and employed a range of epigenetic clocks, most frequently Horvath, GrimAge, and PhenoAge. Risk of bias was assessed using the ROBINS-E tool, with most studies rated as having some concerns, primarily due to a lack of adjustment for key covariates. Meta-analyses of 6 studies using cumulative ACE exposure and standardised regression coefficients revealed no significant associations with EAA for first-generation clocks (Horvath: β =  - 0.03, 95% CI - 0.15 to 0.09; Hannum: β =  - 0.09, 95% CI - 0.41 to 0.23) or second-generation clocks (PhenoAge and GrimAge: both β = 0.21, 95% CIs spanning zero). Narrative synthesis of studies, including those that could not be considered in the meta-analyses, highlighted heterogeneous methodologies and mixed findings, particularly for individual ACEs and third generation clocks such as DunedinPACE. These findings suggest that while ACEs may influence biological aging, current evidence does not support a robust or consistent association with EAA. The study identifies the need for more consistent methodologies in future research.

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by marked epigenetic dysregulation, contributing to aberrant gene expression and tumor progression. To expand current knowledge on genome-wide methylation patterns in ccRCC, we performed Methylated DNA Immunoprecipitation sequencing (MeDIP-seq) on tumor samples from 116 ccRCC patients and 34 adjacent normal renal tissues. We identified differentially methylated regions (DMRs) and integrated these findings with genome-wide copy number alterations.

Results: ccRCC tumors exhibited global hypomethylation combined with focal hypermethylation, particularly within intergenic and repetitive genomic regions. Unsupervised clustering revealed three distinct subtypes, including one subtype characterized by chromosomal instability, synchronous metastasis, and poor survival outcomes. We developed a novel methylation score (MethScore), based on hypermethylated regions, which strongly correlated with disease stage and independently predicted overall survival beyond age and clinical stage. Notably, high methylation levels of specific DMRs were linked to recurrence and advanced disease. Validation with TCGA Kidney Renal Clear Cell Carcinoma methylation data supported the prognostic value of these hypermethylated regions. Additionally, MeDIP-seq accurately detected critical copy number alterations, particularly chromosome 3p loss, which were found in 88% of tumors.

Conclusions: Together, our findings demonstrate that genome-wide methylation profiling can resolve clinically relevant ccRCC subtypes, uncover novel biomarkers of disease aggressiveness, and improve patient risk stratification beyond current clinical models.

Hepatocellular carcinoma (HCC) is a leading global health concern, recognized for its complex pathogenesis and high mortality rates. The metastatic progression of HCC, considered the terminal event in tumor development, plays a pivotal role in determining patient prognosis, with metastasis being a key factor in poor survival outcomes.HDAC11 was found to be highly expressed in HCC tissues, with its elevated expression significantly correlating with poor patient survival. Both in vitro and in vivo experiments demonstrated that silencing HDAC11 led to a marked reduction in HCC cell proliferation. Interestingly, HDAC11 knockdown also resulted in a substantial increase in the metastatic potential of HCC cells. Mass spectrometry analysis revealed that HDAC11 interacts with the NuRD (MTA3) complex. Consistently, immunoprecipitation and GST pull-down assays demonstrated that the N-terminal region of HDAC11 directly binds to MTA3. Moreover, transcriptomic analysis indicated that HDAC11 represses TGFB1 transcription, thereby inhibiting HCC metastasis. The enhanced metastatic phenotype induced by HDAC11 silencing was reversed upon concurrent down-regulation of TGFB1. Moreover, nanoparticles encapsulating both HDAC11 and TGF-β1 inhibitors effectively suppressed HCC cell proliferation and metastasis. This research elucidates the molecular mechanism by which HDAC11 inhibits metastasis and provides an effective strategy to mitigate the side effects associated with HDAC11 inhibition, offering novel insights and approaches for the precision treatment of HCC.

Human Immunodeficiency Virus (HIV) remains a major health challenge despite dramatic advances in treatment and prevention. People living with HIV (PLWH) continue to experience high rates of non-AIDS comorbidities, including cardiovascular, renal, pulmonary, oncologic, and neurocognitive disorders. These conditions persist under viral suppression, underscoring the lasting biological impact of infection. Epigenetic dysregulation has emerged as a key driver of these outcomes. HIV integration, viral proteins, chronic inflammation, and ART exposure have all been reported to alter DNA methylation, histone modifications, transcription factor networks, and non-coding RNA regulation. These changes extend beyond infected cells, reprogramming uninfected immune and tissue compartments. Long-lived cell populations display features of epigenetic aging contributing to chronic inflammation and multimorbidity. Epigenetic clocks consistently reveal accelerated biological aging in PLWH, linking infection to age-related disease risk. Overall, HIV should be viewed not only as a virologic condition but also as one of persistent epigenomic remodeling. Recognizing how durable reprogramming sustains inflammation, accelerates aging, and promotes comorbidity will be critical for advancing beyond viral suppression toward interventions that mitigate long-term health risks in PLWH.

Background: Lifestyle interventions are cornerstones of metabolic dysfunction-associated fatty liver disease (MASLD) management, and differential DNA methylation of potassium voltage-gated channel subfamily Q member 1 (KCNQ1) was involved in MASLD-related diseases. However, little is known about the DNA methylation mechanism of KCNQ1 underlying the effect of lifestyle interventions on the most common liver disease.

Objective: This study aimed to investigate the role of DNA methylation of KCNQ1 in metabolic dysfunction-associated steatohepatitis (MASH) after diet intervention.

Methods: This study utilized 38 male C57BL/6 mice (9-week-old, SPF grade). Following a 1-week acclimatization period, animals were randomly allocated to receive either a methionine-choline deficient (MCD, n = 23) or methionine-choline sufficient (MCS, n = 15) dietary regimen for 4 weeks. Seven mice per group were subsequently euthanized for MASH model validation. After confirming successful model establishment, remaining MASH mice underwent randomized allocation to four-week interventions: low-fat diet (LFD, n = 8), continued MCD feeding (n = 8), or control MCS maintenance (n = 8). Genomic DNA methylation patterns in hepatic and adipose tissues were analyzed using methylation-sensitive restriction enzyme sequencing (MethylRAD). For LFD-treated MASH specimens, EpiTYPER mass spectrometry and quantitative reverse transcription PCR were employed to assess DNA methylation status and transcriptional expression of KCNQ1, respectively.

Results: Hypermethylation in the intron of KCNQ1 was observed after LFD intervention in the liver and adipose tissue of MASH mice (p < 0.05) with MethylRAD sequencing. High DNA methylation and low mRNA expression of KCNQ1 were validated in adipose tissue of MASH mice in response to LFD (p < 0.05) with the EpiTYPER array.

Conclusions: The study reinforced the role of DNA methylation in regulating gene expression of KCNQ1 in response to LFD intervention and highlighted that the DNA methylation of KCNQ1 in MASH adipose tissue could be tissue-specific. All these results contribute to elucidating the molecular mechanisms underlying the activities of DNA methylation in MASH.