• DDP resistance
• RND1
• arachidonic acid
• lung squamous cell carcinoma

• Cell Line
• Hepatocyte Nuclear Factor 3-beta/genetics
• Hepatocyte Nuclear Factor 3-beta/metabolism
• Arachidonic Acid/metabolism
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• rho GTP-Binding Proteins/genetics
• rho GTP-Binding Proteins/metabolism
• Gene Expression Regulation, Neoplastic/drug effects

• 2023JJ60314 Joint Fund Project of Hunan Natural Science Foundation Planning Department

• DNA methyaltion
• Plasmodium falciparum
• TNF
• host parasite interactions
• malaria
• methylome

• New York University Abu Dhabi

Biomarkers allowing characterization of pediatric rhabdomyosarcoma (RMS) are lacking. Epitope detection in monocytes (EDIM) is a novel method focused on detection of the biomarkers TKTL1 (transketolase-like protein 1) and Apo10 (epitope of DNaseX) in activated monocytes (CD14⁺/CD16⁺) from patient’s blood. We investigated the expression of these biomarkers in RMS cell lines, tumor material, and peripheral blood from RMS patients. Expression levels of TKTL1 and DNaseX/Apo10 in RMS cell lines (RH30, RD) and tumor samples were analyzed by RT-PCR and flow cytometry. Blood samples of 29 RMS patients were measured and compared to 27 healthy individuals. The percentages of activated CD14⁺/CD16⁺ monocytes harboring TKTL1 and Apo10 were determined. EDIM-TKTL1 and EDIM-Apo10 expression scores were calculated. The relationship between TKTL1 expression and DNA-hypomethylation was evaluated. Both RMS cell lines and tumor samples showed significantly higher expression levels of TKTL1 and DNaseX/Apo10 compared to skeletal muscle cells (SkMC). EDIM-TKTL1 and EDIM-Apo10 scores were positive in 96.5% of patients with RMS. All healthy controls had negative corresponding scores. RMS cell lines show increased expression levels of the biomarkers TKTL1 and DNaseX/Apo10. The sensitivity of the EDIM blood test indicates that this assay might serve as an additional tool in pediatric RMS.

• Chemotherapy
• Gastric cancer
• Ras
• RhoA
• USP11

Copper (Cu), an essential micronutrient, plays an essential role in several physiological processes, including cell proliferation and angiogenesis; however, its dysregulation induces oxidative stress and inflammatory responses. Significant Cu accumulation is observed in several tumor tissues. The bioavailability of intracellular Cu is tightly controlled by Cu transporters, including Cu transporter 1 (CTR1) and Cu-transporting P-type ATPase α and β (ATP7A and ATP7B), and Cu chaperones, including Cu chaperone for superoxide dismutase 1 (CCS) and antioxidant-1 (Atox-1). In several tumor tissues, these abnormalities that induce intra­cellular Cu accumulation are involved in tumor progression. In addition, functional disturbance in Cu-containing secretory enzymes, such as superoxide dismutase 3 (SOD3), and lysyl oxidase enzymes (LOX and LOXL1–4) with abnormal Cu dynamics plays a key role in tumor metastasis. For example, the loss of SOD3 in tumor tissues induces oxidative stress, which promotes neovascularization and epithelial-to-mesenchymal transition (EMT). LOX promotes collagen crosslinking, which functions in the metastatic niche formation. Accordingly, restricted Cu regulation may be a novel strategy for the inhibition of tumor metastasis. However, it is unclear how these Cu disturbances occur in tumor tissues and the exact molecular mechanisms underlying Cu secretory enzymes. In this review article, I discuss the role of Cu transporters, Cu chaperones, and Cu-containing secretory enzymes in tumor progression to better understand the role of Cu homeostasis in tumor tissues.

Background: The management of gastric cancer (GC) still lacks tumor markers with high specificity and sensitivity. The goal of current research is to find effective diagnostic and prognostic markers and to clarify their related mechanisms.

Methods: In this study, we integrated GC DNA methylation data from publicly available datasets obtained from TCGA and GEO databases, and applied random forest and LASSO analysis methods to screen reliable differential methylation sites (DMSs) for GC diagnosis. We constructed a diagnostic model of GC by logistic analysis and conducted verification and clinical correlation analysis. We screened credible prognostic DMSs through univariate Cox and LASSO analyses and verified a prognostic model of GC by multivariate Cox analysis. Independent prognostic and biological function analyses were performed for the prognostic risk score. We performed TP53 correlation analysis, mutation and prognosis analysis on eleven-DNA methylation driver gene (DMG), and constructed a multifactor regulatory network of key genes.

Results: The five-DMS diagnostic model distinguished GC from normal samples, and diagnostic risk value was significantly correlated with grade and tumor location. The prediction accuracy of the eleven-DMS prognostic model was verified in both the training and validation datasets, indicating its certain potential for GC survival prediction. The survival rate of the high-risk group was significantly lower than that of the low-risk group. The prognostic risk score was an independent risk factor for the prognosis of GC, which was significantly correlated with N stage and tumor location, positively correlated with the VIM gene, and negatively correlated with the CDH1 gene. The expression of CHRNB2 decreased significantly in the TP53 mutation group of gastric cancer patients, and there were significant differences in CCDC69, RASSF2, CHRNB2, ARMC9, and RPN1 between the TP53 mutation group and the TP53 non-mutation group of gastric cancer patients. In addition, CEP290, UBXN8, KDM4A, RPN1 had high frequency mutations and the function of eleven-DMG mutation related genes in GC patients is widely enriched in multiple pathways.

Conclusion: Combined, the five-DMS diagnostic and eleven-DMS prognostic GC models are important tools for accurate and individualized treatment. The study provides direction for exploring potential markers of GC.

• DNA methylation
• diagnosis
• gastric cancer
• mutation
• prognosis
• tumor marker

Gastric cancer (GC) is one of the most lethal malignant tumors. To improve the prognosis of GC, the identification of novel driver genes as therapeutic targets is in urgent need. Here, we aimed to identify novel driver genes and clarify their roles in gastric cancer. OSBPL3 was identified as a candidate driver gene by in silico analysis of public genomic datasets. OSBPL3 expression was analyzed by RT-qPCR and immunohistochemistry in GC cells and tissues. The biological functions and mechanisms of OSBPL3 in GC were examined in vitro and in vivo using GC cells. The association between OSBPL3 expression and clinical outcome in GC patients was also evaluated. Overexpression of OSBPL3 was detected in GC cells with OSBPL3 DNA copy number gains and promoter hypomethylation. OSBPL3-knockdown reduced GC cell growth in vitro and in vivo by inhibiting cell cycle progression. Moreover, an active Ras pull-down assay and western blotting demonstrated that OSBPL3 activates the R-Ras/Akt signaling pathway in GC cells. In a clinical analysis of two GC datasets, high OSBPL3 expression was predictive of a poor prognosis. Our findings suggest that OSBPL3 is a novel driver gene stimulating the R-Ras/Akt signaling pathway and a potential therapeutic target in GC patients.

• Adaptive pathology
• Epigenetic landscape
• Epigenetic regulation
• Inflammation
• Neutrophil oxidants
• Redox epigenomics
• Redox signalling
• Tumour initiation
• Tumour progression

• Epigenesis, Genetic
• Epigenomics
• Oxidants
• Oxidation-Reduction
• Oxidative Stress/genetics

• Cancer
• Copper
• Epigenetics
• Metabolism
• RTK

Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials.

Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies.

Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.

• DNA methylation
• Epigenetic therapy
• Histone methyltransferase
• Immune evasion
• Immunotherapy

DNA methylation has been demonstrated to play significant roles in the etiology and pathogenesis of head and neck squamous cell carcinoma (HNSCC). In the present study, methylation microarray dataset (GSE87053) and gene expression microarray dataset (GSE23558) were downloaded from GEO database and analyzed through R language. A total of 255 hypermethylated-downregulated genes and 114 hypomethylated-upregulated genes were finally identified. Functional enrichment analyses were performed and a comprehensive protein–protein interaction (PPI) network was constructed. Subsequently, the top ten hub genes selected by Cytoscape software were subjected to further analyses. It was illustrated that the expression level of CSF2, CTLA4, ETS1, PIK3CD, and CFTR was intimately associated with HNSCC. Survival analysis suggested that CTLA4 and FGFR2 could serve as effective independent prognostic biomarkers for HNSCC patients. Overall, our study lay a groundwork for further investigation into the underlying molecular mechanisms in HNSCC carcinogenesis, providing potential biomarkers and therapeutic targets for HNSCC.

• DNA methylation
• GEO
• PPI
• biomarker
• head and neck squamous cell carcinoma
• prognosis

• Biomarker
• CRISPR/Cas9
• CRISPR/dCas9
• Chromatin
• Epi-effector
• Epigenetics
• Genetic engineering
• Therapeutics

• CRISPR-Cas9
• DNA methylation
• cancer therapy
• epigenetics
• gene editing

• Chromatin remodeling
• EZH2
• Epigenetics
• Gastric cancer
• Histone modification

• DNA demethylation
• EMT
• activation-induced cytidine deaminase
• clear cell renal cell carcinoma

DNA methylation is the most widely-studied epigenetic modification, playing a critical role in the regulation of gene expression. Dysregulation of DNA methylation is implicated in the pathogenesis of numerous diseases. For example, aberrant DNA methylation in promoter regions of tumor-suppressor genes has been strongly associated with the development and progression of many different tumors. Accordingly, technologies designed to manipulate DNA methylation at specific genomic loci are very important, especially in the context of cancer therapy. Traditionally, epigenomic editing technologies have centered around zinc finger proteins (ZFP)- and transcription activator-like effector protein (TALE)-based targeting. More recently, however, the emergence of clustered regulatory interspaced short palindromic repeats (CRISPR)-deactivated Cas9 (dCas9)-based editing systems have shown to be a more specific and efficient method for the targeted manipulation of DNA methylation. Here, we describe the regulation of the DNA methylome, its significance in cancer and the current state of locus-specific editing technologies for altering DNA methylation.

• CRISPR
• DNA methylation
• cancer
• editing
• epigenetics

The Rho GTPase family can be classified into classic and atypical members. Classic members cycle between an inactive Guanosine DiPhosphate -bound state and an active Guanosine TriPhosphate-bound state. Atypical Rho GTPases, such as RND1, are predominantly in an active GTP-bound conformation. The role of classic members in oncogenesis has been the subject of numerous studies, while that of atypical members has been less explored. Besides the roles of RND1 in healthy tissues, recent data suggest that RND1 is involved in oncogenesis and response to cancer therapeutics. Here, we present the current knowledge on RND1 expression, subcellular localization, and functions in healthy tissues. Then, we review data showing that RND1 expression is dysregulated in tumors, the molecular mechanisms involved in this deregulation, and the role of RND1 in oncogenesis. For several aggressive tumors, RND1 presents the features of a tumor suppressor gene. In these tumors, low expression of RND1 is associated with a bad prognosis for the patients. Finally, we highlight that RND1 expression is induced by anticancer agents and modulates their response. Of note, RND1 mRNA levels in tumors could be used as a predictive marker of both patient prognosis and response to anticancer agents.

• RND
• Rho GTPase
• migration
• oncogenesis
• prognosis factor
• response to anticancer agents

• Carcinogenesis/genetics
• Gene Expression Regulation, Neoplastic/genetics
• Genes, Tumor Suppressor
• Humans
• Neoplasms/genetics
• Neoplasms/pathology
• rho GTP-Binding Proteins/genetics

• PRSS3
• gastric cancer
• metastasis
• prognosis

• DNA methylation
• Epigenetics
• S-adenosylmethionine

• DNA methylation
• SAM
• breast cancer
• epigenetics
• metastasis

• Cancer
• CpG islands
• DNA methylation

• Alternative Splicing
• Animals
• Biomarkers, Tumor/genetics
• CpG Islands/genetics
• DNA Methylation
• Gene Silencing
• Genes, Tumor Suppressor
• Genomic Imprinting
• Humans
• Models, Chemical
• Neoplasms/diagnosis
• Neoplasms/genetics
• Neoplasms/pathology
• Promoter Regions, Genetic
• Transcription, Genetic

• DNA methylation
• anticancer therapies
• epigenetic readers
• epigenetics
• histone acetylation
• histone methylation

• Cancer
• Epi-driver
• Epi-passenger
• Epigenetics
• Metastasis

• Cancer
• Epigenetics
• Receptor tyrosine kinases
• Signal transduction

• Biomarker
• Case-control study
• DAPK1 hypermethylation
• DNA methylation
• Meta-analysis
• Oral cancer

• Cisplatin resistance
• DNA methylation
• Ovarian cancer
• TMEM88
• Wnt

Fibrosis is a progressive and potentially fatal process that can occur in numerous organ systems. Characterised by the excessive deposition of extracellular matrix proteins such as collagens and fibronectin, fibrosis affects normal tissue architecture and impedes organ function. Although a considerable amount of research has focused on the mechanisms underlying disease pathogenesis, current therapeutic options do not directly target the pro-fibrotic process. As a result, there is a clear unmet clinical need to develop new agents. Novel findings implicate a role for epigenetic modifications contributing to the progression of fibrosis by alteration of gene expression profiles.

This review will focus on DNA methylation; its association with fibroblast differentiation and activation and the consequent buildup of fibrotic scar tissue. The potential use of therapies that modulate this epigenetic pathway for the treatment of fibrosis in several organ systems is also discussed.

• 5-aza-2′-deoxycytidine
• 5-azacytidine
• DNA methylation
• Fibroblast
• Fibrosis
• Myofibroblast

R-Ras and cytohesin-2/ARNO coordinate in the control of epithelial cell adhesion, but the mechanism has been unclear. Cytohesin-2/ARNO regulates traffic through an EHD1-positive recycling compartment. Inhibition of cytohesin-2/ARNO activity traps R-Ras and integrins within the EHD1 compartment and impairs adhesion and spreading.

When expressed in epithelial cells, cytohesin-2/ARNO, a guanine nucleotide exchange factor (GEF) for ARF small GTPases, causes a robust migration response. Recent evidence suggests that cytohesin-2/ARNO acts downstream of small the GTPase R-Ras to promote spreading and migration. We hypothesized that cytohesin-2/ARNO could transmit R-Ras signals by regulating the recycling of R-Ras through ARF activation. We found that Eps15-homology domain 1 (EHD1), a protein that associates with the endocytic recycling compartment (ERC), colocalizes with active R-Ras in transiently expressed HeLa cells. In addition, we show that EHD1-positive recycling endosomes are a novel compartment for cytohesin-2/ARNO. Knockdown or expression of GEF-inactive (E156K) cytohesin-2/ARNO causes R-Ras to accumulate on recycling endosomes containing EHD1 and inhibits cell spreading. E156K-ARNO also causes a reduction in focal adhesion size and number. Finally, we demonstrate that R-Ras/ARNO signaling is required for recycling of α5-integrin and R-Ras to the plasma membrane. These data establish a role for cytohesin-2/ARNO as a regulator of R-Ras and integrin recycling and suggest that ARF-regulated trafficking of R-Ras is required for R-Ras–dependent effects on spreading and adhesion formation.

The R-ras gene encodes a small GTPase that is a member of the Ras family. Despite close sequence similarities, R-Ras is functionally distinct from the prototypic Ras proteins; no transformative activity and no activating mutations of R-Ras in human malignancies have been reported for it. R-Ras activity appears inhibitory towards tumour proliferation and invasion, and to promote cellular quiescence. Contrary to this, using mice with a deletion of the R-ras gene, we found that R-Ras facilitates DMBA/TPA-induced skin tumour induction. The tumours appeared in wild-type (WT) mice on average 6 weeks earlier than in R-Ras knockout (R-Ras KO) mice. WT mice developed almost 6 times more tumours than R-Ras KO mice. Despite strong R-Ras protein expression in the dermal blood vessels, no R-Ras could be detected in the epidermis from where the tumours arose. The DMBA/TPA skin tumourigenesis-model is highly dependent upon inflammation, and we found a greatly attenuated skin inflammatory response to DMBA/TPA-treatment in the R-Ras KO mice in the context of leukocyte infiltration and proinflammatory cytokine expression. Thus, these data suggest that despite its characterised role in promoting cellular quiescence, R-Ras is pro-tumourigenic in the DMBA/TPA tumour model and important for the inflammatory response to DMBA/TPA treatment.

• DNA methylation
• cancer
• discordant monozygotic twins
• environment
• epigenetics
• twin study

The Rac-GEF P-REX1 is a key mediator of ErbB signaling in breast cancer recently implicated in mammary tumorigenesis and metastatic dissemination. Although P-REX1 is essentially undetectable in normal human mammary epithelial tissue, this Rac-GEF is markedly upregulated in human breast carcinomas, particularly of the luminal subtype. The mechanisms underlying P-REX1 upregulation in breast cancer are unknown. Toward the goal of dissecting the mechanistic basis of P-REX1 overexpression in breast cancer, in this study we focused on the analysis of methylation of the PREX1 gene promoter.

To determine the methylation status of the PREX1 promoter region, we used bisulfite genomic sequencing and pyrosequencing approaches. Re-expression studies in cell lines were carried out by treatment of breast cancer cells with the demethylating agent 5-aza-2′-deoxycitidine. PREX1 gene methylation in different human breast cancer subtypes was analyzed from the TCGA database.

We found that the human PREX1 gene promoter has a CpG island located between -1.2 kb and +1.4 kb, and that DNA methylation in this region inversely correlates with P-REX1 expression in human breast cancer cell lines. A comprehensive analysis of human breast cancer cell lines and tumors revealed significant hypomethylation of the PREX1 promoter in ER-positive, luminal subtype, whereas hypermethylation occurs in basal-like breast cancer. Treatment of normal MCF-10A or basal-like cancer cells, MDA-MB-231 with the demethylating agent 5-aza-2′-deoxycitidine in combination with the histone deacetylase inhibitor trichostatin A restores P-REX1 levels to those observed in luminal breast cancer cell lines, suggesting that aberrant expression of P-REX1 in luminal breast cancer is a consequence of PREX1 promoter demethylation. Unlike PREX1, the pro-metastatic Rho/Rac-GEF, VAV3, is not regulated by methylation. Notably, PREX1 gene promoter hypomethylation is a prognostic marker of poor patient survival.

Our study identified for the first time gene promoter hypomethylation as a distinctive subtype-specific mechanism for controlling the expression of a key regulator of Rac-mediated motility and metastasis in breast cancer.

The online version of this article (doi:10.1186/s13058-014-0441-7) contains supplementary material, which is available to authorized users.

• DNMT inhibitors
• Epigenetic modifications
• Epigenetic therapy
• HDAC inhibitors
• Hepatocellular carcinoma
• Natural products

• Animals
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Epigenesis, Genetic
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics

One of the biggest roadblocks to using stem cells as the basis for regenerative medicine therapies is the tumorigenicity of stem cells. Unfortunately, the unique abilities of stem cells to self-renew and differentiate into a variety of cell types are also mechanistically linked to their tumorigenic behaviors. Understanding the mechanisms underlying the close relationship between stem cells and cancer cells has therefore become a primary goal in the field. In addition, knowledge gained from investigating the striking parallels between mechanisms orchestrating normal embryogenesis and those that invoke tumorigenesis may well serve as the foundation for developing novel cancer treatments. Emerging discoveries have demonstrated that epigenetic regulatory machinery plays important roles in normal stem cell functions, cancer development, and cancer stem cell identity. These studies provide valuable insights into both the shared and distinct mechanisms by which pluripotency and oncogenicity are established and regulated. In this review, the cancer-related epigenetic mechanisms found in pluripotent stem cells and cancer stem cells will be discussed, focusing on both the similarities and the differences.

• Amino Acid Sequence
• Magnetic Resonance Spectroscopy
• Nuclear Magnetic Resonance, Biomolecular
• Protein Structure, Secondary
• rho GTP-Binding Proteins/chemistry

• 1R01GM092851 NIGMS NIH HHS
• 1R01GM73071 NIGMS NIH HHS

• Amplification
• Excision repair cross-complementing 1
• Fluorescence in situ hybridization
• High polysomy
• Prognosis

• 12-O-tetradecanoylphorbol-13-acetate
• DNA methylation
• Differentiation
• Extracellular-superoxide dismutase
• Histone acetylation

• Azacitidine/pharmacology
• Cell Line, Tumor
• DNA Methylation
• Epigenesis, Genetic
• Extracellular Space/enzymology
• Histones/metabolism
• Humans
• Monocytes/enzymology
• Superoxide Dismutase/genetics
• Tetradecanoylphorbol Acetate/pharmacology

• epigenetics
• glioma
• dna methylation
• central nervous system (cns)
• differentiation
• cancer stem cells

• Animals
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Brain Neoplasms/pathology
• Carcinogenesis/genetics
• Cell Differentiation
• Chromatin Assembly and Disassembly
• DNA Methylation
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Glioblastoma/drug therapy
• Glioblastoma/genetics
• Glioblastoma/pathology
• Humans
• Molecular Targeted Therapy
• Neoplastic Stem Cells/physiology

• Wellcome Trust
• Cancer Research UK

• Cell Line, Tumor
• CpG Islands
• DNA Methylation
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Genome
• Histones/metabolism
• Humans
• Male
• MicroRNAs/genetics
• MicroRNAs/physiology
• Promoter Regions, Genetic
• Prostatic Neoplasms/genetics