scholarly journals Influence of Benzo(a)pyrene on Different Epigenetic Processes

2021 ◽  
Vol 22 (24) ◽  
pp. 13453
Author(s):  
Bożena Bukowska ◽  
Paulina Sicińska
Keyword(s):  
Lung Cancer ◽  
Dna Methylation ◽  
Histone Deacetylases ◽  
Polyaromatic Hydrocarbons ◽  
Methylation Status ◽  
Underlying Mechanism ◽  
Epidemiological Studies ◽  
Dna Methyltransferases ◽  
Epigenetic Changes ◽  
Marine Medaka

Epigenetic changes constitute one of the processes that is involved in the mechanisms of carcinogenicity. They include dysregulation of DNA methylation processes, disruption of post-translational patterns of histone modifications, and changes in the composition and/or organization of chromatin. Benzo(a)pyrene (BaP) influences DNA methylation and, depending on its concentrations, as well as the type of cell, tissue and organism it causes hypomethylation or hypermethylation. Moreover, the exposure to polyaromatic hydrocarbons (PAHs), including BaP in tobacco smoke results in an altered methylation status of the offsprings. Researches have indicated a potential relationship between toxicity of BaP and deregulation of the biotin homeostasis pathway that plays an important role in the process of carcinogenesis. Animal studies have shown that parental-induced BaP toxicity can be passed on to the F1 generation as studied on marine medaka (Oryzias melastigma), and the underlying mechanism is likely related to a disturbance in the circadian rhythm. In addition, ancestral exposure of fish to BaP may cause intergenerational osteotoxicity in non-exposed F3 offsprings. Epidemiological studies of lung cancer have indicated that exposure to BaP is associated with changes in methylation levels at 15 CpG; therefore, changes in DNA methylation may be considered as potential mediators of BaP-induced lung cancer. The mechanism of epigenetic changes induced by BaP are mainly due to the formation of CpG-BPDE adducts, between metabolite of BaP—BPDE and CpG, which leads to changes in the level of 5-methylcytosine. BaP also acts through inhibition of DNA methyltransferases activity, as well as by increasing histone deacetylases HDACs, i.e., HDAC2 and HDAC3 activity. The aim of this review is to discuss the mechanism of the epigenetic action of BaP on the basis of the latest publications.

scholarly journals Frequent DNA methylation changes in cancerous and noncancerous lung tissues from smokers with non-small cell lung cancer

Mutagenesis ◽  
2020 ◽  
Author(s):  
Kristina Daniunaite ◽  
Agne Sestokaite ◽  
Raimonda Kubiliute ◽  
Kristina Stuopelyte ◽  
Eeva Kettunen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Methylation ◽  
Methylation Status ◽  
Small Cell ◽  
Study Cohort ◽  
Tumour Suppressor Genes ◽  
Epigenetic Changes ◽  
Small Cell Lung ◽  
Specific Pcr ◽  
Never Smokers

Abstract Cancer deaths account for nearly 10 million deaths worldwide each year, with lung cancer (LCa) as the leading cause of cancer-related death. Smoking is one of the major LCa risk factors, and tobacco-related carcinogens are potent mutagens and epi-mutagens. In the present study, we aimed to analyse smoking-related epigenetic changes in lung tissues from LCa cases. The study cohort consisted of paired LCa and noncancerous lung tissues (NLT) from 104 patients, 90 of whom were smokers or ex-smokers (i.e. ever smokers) at the time of diagnosis. DNA methylation status of tumour suppressor genes DAPK1, MGMT, p16, RASSF1 and RARB was screened by means of methylation-specific PCR (MSP) and further analysed quantitatively by pyrosequencing. Methylation of at least one gene was detected in 59% (61 of 104) of LCa samples and in 39% (41 of 104) of NLT. DAPK1 and RASSF1 were more frequently methylated in LCa than in NLT (P = 0.022 and P = 0.041, respectively). The levels of DNA methylation were higher in LCa than NLT at most of the analysed CpG positions. More frequent methylation of at least one gene was observed in LCa samples of ever smokers (63%, 57 of 90) as compared with never smokers (36%, 5 of 14; P = 0.019). In the ever smokers group, methylation of the genes also occurred in NLT, but was rare or absent in the samples of never smokers. Among the current smokers, RASSF1 methylation in LCa showed association with the number of cigarettes smoked per day (P = 0.017), whereas in NLT it was positively associated with the duration of smoking (P = 0.039). Similarly, p16 methylation in LCa of current smokers correlated with the larger number of cigarettes smoked per day (P = 0.047). Overall, DNA methylation changes were present in both cancerous and noncancerous tissues of LCa patients and showed associations with smoking-related parameters.

Expression of ATRA Inducible RARα2 Isoform Is Deregulated in AML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1204-1204
Author(s):  
Annegret Glasow ◽  
Angela Barrett ◽  
Rajeev Gupta ◽  
David Grimwade ◽  
Marieke von Lindern ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Cell Types ◽  
Dna Methyltransferases ◽  
Protein Isoforms ◽  
Epigenetic Changes

Abstract Retinoids exert a variety of effects on both normal and malignant hematopoietic cells. To date, three different retinoic acid receptor (RAR) and retinoid X receptor (RXR) genes have been characterized, each encoding multiple N-terminal protein isoforms. RXRs serve as co-regulators for RARs, and many other nuclear receptors integrating different signalling pathways. All-trans-retinoic acid (ATRA) signaling pathway is of critical importance for optimal myelomonocytic differentiation and its disruption by translocations of the RARα gene leads to acute promyelocytic leukemia (APL). APL associated fusion oncoproteins, such as PML-RARα and PLZF-RARα, function through recruitment of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), thus promoting an inactive chromatin state and leading to repression of RARα target genes. Recently, we demonstrated that up-regulation of RARα2 expression by ATRA directly correlates with differentiation of APL and non-APL AML cells and that RARα2 transcription is silenced by DNA methylation in AML cell lines. Using primary AML samples as well as normal cord and peripheral blood derived cells representing different stages of myelomonocytic development we now show that expression of RARα2 increases with maturation of hematopietic cells. Expression of RARα1 on the other hand, which is transcribed from a distinct promoter, remains relatively constant throughout the different stages of myelomonocytic development. The levels of RARα1 expression in various primary AML cell types appear to be similar to those found in normal hematopietic cells. Consistent with data derived from AML cell lines, however, the RARα2 isoform is poorly expressed in all samples. Compared with CD34+/CD133+ or CD34+ progenitors, and more mature CD33+ myeloid cells, RARα2 is expressed at much lower levels in a variety of primary AML cells and its expression is not effectively induced by myelomonocytic growth factors and/or ATRA. Negatively acting epigenetic changes, such as DNA methylation, appear to be responsible for deregulated expression of RARα2 in AML cells, although their pattern and extent differs significantly between AML cell lines and primary AML samples. Taken together our data suggest that agents, which revert negatively acting epigenetic changes may restore expression of the RARα2 isoform in AML cells and render them more responsive to ATRA as well as other differentiation inducers.

scholarly journals Immunological Effects of Epigenetic Modifiers

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1911 ◽  
Author(s):  
Lucillia Bezu ◽  
Alejandra Wu Chuang ◽  
Peng Liu ◽  
Guido Kroemer ◽  
Oliver Kepp
Keyword(s):  
Dna Methylation ◽  
Histone Deacetylases ◽  
Methylation Status ◽  
Dna Methyltransferases ◽  
Cancer Hallmarks ◽  
Epigenetic Modifiers ◽  
Oncogenic Pathways ◽  
Immunotherapeutic Strategy ◽  
Immunological Effects ◽  
Molecular Patterns

Epigenetic alterations are associated with major pathologies including cancer. Epigenetic dysregulation, such as aberrant histone acetylation, altered DNA methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. Targeting epigenetic cancer hallmarks can be harnessed as an immunotherapeutic strategy, exemplified by the use of pharmacological inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) that can result in the release from the tumor of danger-associated molecular patterns (DAMPs) on one hand and can (re-)activate the expression of tumor-associated antigens on the other hand. This finding suggests that epigenetic modifiers and more specifically the DNA methylation status may change the interaction of chromatin with chaperon proteins including HMGB1, thereby contributing to the antitumor immune response. In this review, we detail how epigenetic modifiers can be used for stimulating therapeutically relevant anticancer immunity when used as stand-alone treatments or in combination with established immunotherapies.

scholarly journals Epigenetic determinants in rheumatoid arthritis: the influence of DNA methylation and histone modifications

2017 ◽  
Vol 71 (0) ◽  
pp. 0-0
Author(s):  
Bogdan Kolarz ◽  
Maria Majdan
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Histone Modifications ◽  
Histone Deacetylases ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanisms ◽  
Epigenetic Changes ◽  
Genetic Changes ◽  
Post Translational Modifications ◽  
Methylation Of Dna

Epigenetics is a field of science which describes external and environmental modifications to DNA without altering their primary sequences of nucleotides. Contrary to genetic changes, epigenetic modifications are reversible. The epigenetic changes appear as a result of the influence of external factors, such as diet or stress. Epigenetic mechanisms alter the accessibility of DNA by methylation of DNA or post-translational modifications of histones (acetylation, methylation, phosphorylation, ubiquitinqation). The extent of DNA methylation depends on the balance between DNA methyltransferases and demethylases. The main histone modifications are stimulated by K-acetyltransferases, histone deacetylases, K-metyltransferases and K-demethylases. There is proof that environmental modifications of this enzymes regulate immunological processes including autoimmunity in rheumatoid arthritis (RA). In this work we present epigenetic mechanisms involved in RA pathogenesis and a range of research presenting the possible impact of its modification in RA patients.

scholarly journals Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

2018 ◽  
Vol 19 (10) ◽  
pp. 3106 ◽  
Author(s):  
Kuniyasu Soda
Keyword(s):  
Dna Methylation ◽  
Carbon Metabolism ◽  
Methylation Status ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Dna Methyltransferases ◽  
Polyamine Metabolism ◽  
Methyl Group ◽  
Wide Range ◽  
One Carbon Metabolism

Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.

P.2.e.017 DNA methylation is selectively altered in bipolar disorder and linked to DNA methyltransferases and histone deacetylases mRNAs levels

2012 ◽  
Vol 22 ◽  
pp. S285-S286
Author(s):  
C. D'Addario ◽  
B. Dell'Osso ◽  
A. Di Francesco ◽  
M.C. Palazzo ◽  
B. Benatti ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bipolar Disorder ◽  
Histone Deacetylases ◽  
Dna Methyltransferases

PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice

2019 ◽  
Vol 78 (10) ◽  
pp. 1420-1429 ◽  
Author(s):  
Xiaobo Zhu ◽  
Fang Chen ◽  
Ke Lu ◽  
Ai Wei ◽  
Qing Jiang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Knockout Mice ◽  
Cartilage Damage ◽  
Critical Role ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Dna Methyltransferases ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Peroxisome Proliferator

ObjectivesOsteoarthritis (OA) is the most common degenerative joint disease in aged population and its development is significantly influenced by aberrant epigenetic modifications of numerous OA susceptible genes; however, the precise mechanisms that DNA methylation alterations affect OA pathogenesis remain undefined. This study investigates the critical role of epigenetic PPARγ (peroxisome proliferator–activated receptor-gamma) suppression in OA development.MethodsArticular cartilage expressions of PPARγ and bioactive DNA methyltransferases (DNMTs) from OA patients and mice incurred by DMM (destabilisation of medial meniscus) were examined. DNA methylation status of both human and mouse PPARγ promoters were assessed by methylated specific PCR and/or bisulfite-sequencing PCR. OA protections by a pharmacological DNA demethylating agent 5Aza (5-Aza-2'-deoxycytidine) were compared between wild type and PPARγ knockout mice.ResultsArticular cartilages from both OA patients and DMM mice display substantial PPARγ suppressions likely due to aberrant elevations of DNMT1 and DNMT3a and consequential PPARγ promoter hypermethylation. 5Aza known to inhibit both DNMT1 and DNMT3a reversed the PPARγ promoter hypermethylation, recovered the PPARγ loss and effectively attenuated the cartilage damage in OA mice. 5Aza also inhibited the OA-associated excessive inflammatory cytokines and deficit anti-oxidant enzymes, which were blocked by a specific PPARγ inhibitor in cultured chondrocytes. Further, 5Aza-confered protections against the cartilage damage and the associated abnormalities of OA-susceptible factors were significantly abrogated in PPARγ knockout mice.ConclusionEpigenetic PPARγ suppression plays a key role in OA development and PPARγ preservation via promoter demethylation possesses promising therapeutic potentials in clinical treatment of OA and the related joint diseases.

Prostacyclin synthase (PTGIS) expression and epigenetic regulation in non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22160-e22160
Author(s):  
S. G. Gray ◽  
M. C. Cathcart ◽  
N. Al-Sarraf ◽  
G. P. Pidgeon ◽  
K. J. O'Byrne
Keyword(s):  
Lung Cancer ◽  
Cell Lines ◽  
Epigenetic Regulation ◽  
Histone Deacetylases ◽  
Translational Regulation ◽  
Expression Patterns ◽  
Dna Methyltransferases ◽  
Variable Expression ◽  
Oncology Research ◽  
Prostacyclin Synthase

e22160 Background: Prostacyclin synthase (PTGIS) inhibits platelet aggregation and promotes vasodilation. Overexpression of this gene has been shown to inhibit lung cancer growth in a mouse model. Hypermethylation of the PTGIS promoter resulting in downregulation of PTGIS expression has been implicated in colorectal cancer. In this study we have examined both the expression patterns and epigenetic regulation of PTGIS in NSCLC. Methods: DNA/RNA and protein was extracted from matched tumour/normal samples (Thoracic Oncology Research Group BioBank, St James Hospital). PTGIS in these samples and a panel of retrospective resected lung samples was examined by immunohistochemistry and western blotting. A panel of NSCLC cell lines were treated with inhibitors to histone deacetylases (HDi) and DNA methyltransferases (DNMTi) and PTGIS expression examined by RT-PCR. Chromatin immunoprecipitation (ChIP) was used to examine changes to the PTGIS promoter in response to HDi. Results: PTGIS was found to have variable expression in both tumour samples and a panel of lung cancer cell lines. PTGIS expression was demonstrated in the vascular endothelial and bronchial epithelial cells of normal and cancerous sections. A striking variation in intratumoural PTGIS expression was observed. Methylation analysis of cell lines demonstrated hypermethylation of the PTGIS promoter. Treating cells with epigenetic inhibitors resulted in significant upregulation of PTGIS expression. Direct chromatin remodelling of the PTGIS promoter was confirmed. Conclusions: PTGIS is epigenetically regulated. The discrepancy between PTGIS mRNA and protein levels in tumor samples indicates that post-transcriptional and post-translational regulation of PTGIS is central to expression and requires further elucidation. Increased PTGIS expression is a potential therapeutic strategy for tumour prevention. [Table: see text]

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