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1.
Protein & Cell ; (12): 29-38, 2021.
Article in English | WPRIM | ID: wpr-880916

ABSTRACT

Prostate cancer is the most commonly diagnosed non-cutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions.


Subject(s)
Amino Acid Sequence , Epigenesis, Genetic , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Hepatocyte Nuclear Factor 3-alpha/metabolism , Histone Demethylases/metabolism , Histones/metabolism , Humans , Male , Mutation , Prostate/pathology , Prostatic Neoplasms/pathology , Protein Binding , Protein Processing, Post-Translational , Receptors, Androgen/metabolism , Signal Transduction , Transcription, Genetic
2.
Protein & Cell ; (12): 7-28, 2021.
Article in English | WPRIM | ID: wpr-880895

ABSTRACT

Mammalian fertilization begins with the fusion of two specialized gametes, followed by major epigenetic remodeling leading to the formation of a totipotent embryo. During the development of the pre-implantation embryo, precise reprogramming progress is a prerequisite for avoiding developmental defects or embryonic lethality, but the underlying molecular mechanisms remain elusive. For the past few years, unprecedented breakthroughs have been made in mapping the regulatory network of dynamic epigenomes during mammalian early embryo development, taking advantage of multiple advances and innovations in low-input genome-wide chromatin analysis technologies. The aim of this review is to highlight the most recent progress in understanding the mechanisms of epigenetic remodeling during early embryogenesis in mammals, including DNA methylation, histone modifications, chromatin accessibility and 3D chromatin organization.


Subject(s)
Animals , Chromatin Assembly and Disassembly , DNA Methylation , DNA Transposable Elements , Embryo, Mammalian , Embryonic Development/genetics , Epigenesis, Genetic , Epigenome , Female , Fertilization/physiology , Gene Expression Regulation, Developmental , Histone Code , Histones/metabolism , Male , Mice , Oocytes/metabolism , Spermatozoa/metabolism
3.
Article in Chinese | WPRIM | ID: wpr-879490

ABSTRACT

With the in-depth exploration of all stages in early-stage embryos, in particular zygotic genome activation and first cell lineage differentiation, researchers have found that early embryonic epigenetics follows a strict pattern of temporal and spatial modification. Previous studies have determined the inhibitory effect of H3K9me3 and H3K27me3 on genomic expression, and found that they are involved in many core biological events in the genome such as chromatin reprogramming, genomic imprinting, maintenance of embryonic stem cell pluripotency and somatic cell nuclear transfer, though the detailed molecular mechanism has remained elusive. From the point of developmental biology and epigenetics, this article has expounded the research progress on the methylation of H3K9 and H3K27 histones in early-stage embryos, which may provide a clue for the complex mechanism of embryonic development and improvement of culture method for embryos in vitro.


Subject(s)
Chromatin , Embryonic Development , Epigenesis, Genetic , Female , Gene Expression Regulation, Developmental , Histones/metabolism , Humans , Methylation , Pregnancy
4.
Biol. Res ; 50: 27, 2017. graf
Article in English | LILACS | ID: biblio-950878

ABSTRACT

BACKGROUND: miR-22 has been shown to be frequently downregulated and act as a tumor suppressor in multiple cancers including breast cancers. However, the role of miR-22 in regulating the radioresistance of breast cancer cells, as well as its underlying mechanism is still not well understood. METHODS: The expressions of miR-22 and sirt1 at mRNA and protein levels were examined by qRT-PCR and Western Blot. The effects of miR-22 overexpression and sirt1 knockdown on cell viability, apoptosis, radiosensitivity, γ-H2AX foci formation were evaluated by CCK-8 assay, flow cytometry, colony formation assay, and γ-H2AX foci formation assay, respectively. Luciferase reporter assay and qRT-PCR analysis were performed to confirm the interaction between miR-22 and sirt1. RESULTS: miR-22 was downregulated and sirt1 was upregulated at both mRNA and protein levels in breast cancer cells. miR-22 overexpression or sirt1 knockdown significantly suppressed viability, induced apoptosis, reduced survival fraction, and increased the number of γ-H2AX foci in breast cancer cells. Sirt1 was identified as a target of miR-22 and miR-22 negatively regulated sirt1 expression. Ectopic expression of sirt1 dramatically reversed the inhibitory effect of miR-22 on cell viability and promotive effect on apoptotic rates and radiosensitivity in breast cancer cells. CONCLUSIONS: miR-22 suppresses tumorigenesis and improves radiosensitivity of breast cancer cells by targeting sirt1, providing a promising therapeutic target for breast cancer.


Subject(s)
Humans , Female , Radiation Tolerance , Breast Neoplasms/radiotherapy , MicroRNAs/metabolism , Sirtuin 1/metabolism , Radiotherapy Dosage , Breast Neoplasms/metabolism , Histones/metabolism , Down-Regulation , Gene Expression Regulation, Neoplastic , Cell Survival , Apoptosis/genetics , Cell Line, Tumor , Gene Knockdown Techniques , Sirtuin 1/genetics
5.
Einstein (Säo Paulo) ; 13(2): 221-225, Apr-Jun/2015. tab
Article in English | LILACS | ID: lil-751414

ABSTRACT

ABSTRACT Objective: To assess adherence of the prescribing physicians in a private cancer care center to the American Society of Clinical Oncology guideline for antiemetic prophylaxis, in the first cycle of antineoplastic chemotherapy. Methods: A total of 139 chemotherapy regimens, of 105 patients, were evaluated retrospectively from 2011 to 2013. Results: We observed 78% of non-adherence to the guideline rate. The main disagreements with the directive were the prescription of higher doses of dexamethasone and excessive use of 5-HT3 antagonist for low risk emetogenic chemotherapy regimens. On univariate analysis, hematological malignancies (p=0.005), the use of two or more chemotherapy (p=0.05) and high emetogenic risk regimes (p=0.012) were factors statistically associated with greater adherence to guidelines. Treatment based on paclitaxel was the only significant risk factor for non-adherence (p=0.02). By multivariate analysis, the chemotherapy of high emetogenic risk most correlated with adherence to guideline (p=0.05). Conclusion: We concluded that the adherence to guidelines is greater if the chemotherapy regime has high emetogenic risk. Educational efforts should focus more intensely on the management of chemotherapy regimens with low and moderate emetogenic potential. Perhaps the development of a computer generated reminder may improve the adherence to guidelines. .


RESUMO Objetivo: Avaliar a adesão dos médicos prescritores, de um centro privado especializado em oncologia, à diretriz de antiêmese profilática da American Society of Clinical Oncology, no primeiro ciclo de quimioterapia antineoplásica. Métodos: Foram avaliados retrospectivamente 139 esquemas de quimioterapia, de 105 pacientes, tratados no período de 2011 a 2013. Resultados: Foram observados 78% de taxa de não adesão à diretriz. As principais discordâncias com a diretriz foram prescrição de doses mais elevadas de dexametasona e uso excessivo de antagonista 5-HT3 para regimes de quimioterapia de risco emetogênico baixo. Pela análise univariada, malignidades hematológicas (p=0,005), uso de dois ou mais quimioterápicos (p=0,05) e regimes de alto risco emetogênico (p=0,012) foram fatores estatisticamente associados a maior adesão à diretriz. O tratamento baseado em paclitaxel foi o único fator estatisticamente significativo para a não adesão (p=0,02). Pela análise multivariada, a quimioterapia de alto risco emetogênico apresentou maior correlação com a adesão à diretriz (p=0,05). Conclusão: Houve maior aderência para a quimioterapia de alto risco emetogênico. Esforços educacionais devem se concentrar mais intensamente na gestão de regimes de quimioterapia com potencial emetogênico baixo e moderado. Talvez o desenvolvimento de lembretes gerados por sistemas informatizados possa melhorar a aderência à diretriz. .


Subject(s)
Animals , Humans , Mice , DNA Damage , Recombinational DNA Repair , Ubiquitin-Protein Ligases/chemistry , Amino Acid Motifs , Amino Acid Sequence , BRCA1 Protein/antagonists & inhibitors , Cell Line , Chromosome Breakage , Conserved Sequence , DNA Repair , DNA-Binding Proteins/antagonists & inhibitors , Deoxyribonucleases/metabolism , Histones/metabolism , Protein Structure, Tertiary , Ubiquitination , Ubiquitin-Protein Ligases/metabolism
6.
Braz. j. phys. ther. (Impr.) ; 19(2): 105-113, 27/04/2015. tab, graf
Article in English | LILACS | ID: lil-745814

ABSTRACT

Objective: To verify whether 30 minutes of rest between two incremental shuttle walking tests (ISWT) are enough for cardiovascular variables and perceived exertion to return to baseline values in healthy subjects in a broad age range. Method: The maximal exercise capacity of 334 apparently healthy subjects (age ≥18) was evaluated using the ISWT. The test was performed twice with 30 minutes of rest in between. Heart rate (HR), arterial blood pressure (ABP), dyspnea, and leg fatigue were evaluated before and after each test. Subjects were allocated to 6 groups according to their age: G1: 18-29 years; G2: 30-39 years; G3: 40-49 years; G4: 50-59 years; G5: 60-69 years and G6: ≥70 years. Results: All groups had a good performance in the ISWT (median >90% of the predicted distance). The initial HR (HRi) of the second ISWT was higher than the first ISWT in the total sample (p<0.0001), as well as in all groups (p<0.0001). No difference was observed in the behavior of ABP (systolic and diastolic) and dyspnea between the two tests, but this difference occurred for leg fatigue (greater before the second ISWT) in G1 (p<0.05). Most subjects (58%) performed better in the second test. Conclusion: 30 minutes of rest between two ISWTs are not enough for all cardiovascular variables and perceived exertion to return to baseline values. However, this period appears to be sufficient for blood pressure and performance to recover in most subjects. .


Subject(s)
Humans , Nucleosomes/chemistry , Nucleosomes/metabolism , Polycomb Repressive Complex 1/chemistry , Polycomb Repressive Complex 1/metabolism , Ubiquitination , Crystallography, X-Ray , DNA , Histones/chemistry , Histones/metabolism , Models, Molecular , Ubiquitin-Conjugating Enzymes/chemistry , Ubiquitin-Conjugating Enzymes/metabolism , Ubiquitin-Protein Ligases/chemistry , Ubiquitin-Protein Ligases/metabolism
7.
Ciênc. saúde coletiva ; 20(3): 865-874, 03/2015. tab
Article in Portuguese | LILACS | ID: lil-742255

ABSTRACT

Pacientes com diabetes mellitus requerem um autocuidado extenso, com tratamentos complexos e comportamentos de saúde adequados, sendo, essas habilidades, fator chave. Frente a tal complexidade surge a importância do letramento funcional em saúde. O objetivo do estudo foi analisar fatores associados ao letramento em saúde e sua relação com controle glicêmico em pacientes diabéticos. Este estudo foi realizado com 82 pacientes diabéticos tipo 2, atendidos em um ambulatório de endocrinologia de um hospital público, de ambos os sexos e com idade entre 19 e 59 anos, que responderam à versão abreviada e traduzida do Test of Functional Health Literacy in Adults (b-TOFHLA). Valores de glicemia de jejum e hemoglobina glicada foram coletados dos prontuários dos participantes. Foram realizadas correlações, comparações de médias e modelos de regressão linear. O letramento inadequado foi encontrado em 65,9% dos pacientes. Foram fatores associados à pontuação do b-TOFHLA, a idade e os anos de estudos. O letramento global não explicou o controle glicêmico, mas o numeramento apresentou associação com tal controle. Nossos resultados apontam para a necessidade de melhorar o numeramento em saúde dos pacientes para obter seu melhor controle glicêmico, principalmente naqueles com maior idade e menos anos de estudo.


Diabetes mellitus patients must concentrate on self-care, with complex treatments and adequate health behavior in which such habits are a key factor. Due to the complexity of this issue, the importance of literacy in health arises. The goal of the study was to analyze factors associated with literacy in health and its relation with glycemic control in diabetic patients. It involved a study with 82 type 2 diabetic patients of both sexes and aged between 19 and 59 attended in the outpatient endocrinology ward of a public hospital, who filled out an abbreviated and translated version of the Test of Functional Health Literacy in Adults (b-TOFHLA). Fasting glycaemia values and glycated hemoglobin were collected from the clinical history of the participants. Correlations, mean comparisons and linear regression models were tested. Inadequate literacy in health was encountered in 65.9% of the patients. The issues involved factors associated with the b-TOFHLA point scores were age and years of schooling. Global literacy did not explain the glycemic control, but the level of numeracy presented an association with this control. The results point to the need to improve the numeracy in health of the patients to obtain enhanced glycemic control, mainly in those with more advanced age and less years of schooling.


Subject(s)
Histones/metabolism , Nuclear Proteins/genetics , Promoter Regions, Genetic , Saccharomyces cerevisiae Proteins/genetics , Transcriptional Elongation Factors/genetics , Saccharomyces cerevisiae/genetics
8.
Article in English | WPRIM | ID: wpr-183085

ABSTRACT

A growing body of evidence suggests that epigenetic modifications are promising potential mechanisms in cancer research. Among the molecules that mediate epigenetic mechanisms, histone deacetylases (HDACs) are critical regulators of gene expression that promote formation of heterochromatin by deacetylating histone and non-histone proteins. Aberrant regulation of HDACs contributes to malignant transformation and progression in a wide variety of human cancers, including hepatocellular carcinoma (HCC), gastric cancer, lung cancer, and other cancers. Thus, the roles of HDACs have been extensively studied because of their potential as therapeutic targets. However, the underlying mechanism leading to deregulation of individual HDACs remains largely unknown. Some reports have suggested that functional microRNAs (miRNAs) modulate epigenetic effector molecules including HDACs. Here, we describe the oncogenic or tumor suppressive functions of HDAC families and their regulatory miRNAs governing HDAC expression in hepatocarcinogenesis.


Subject(s)
Carcinogenesis/genetics , Carcinoma, Hepatocellular/genetics , Epigenesis, Genetic/genetics , Gene Expression Regulation, Neoplastic/genetics , Histone Deacetylases/genetics , Histones/metabolism , Humans , Liver Neoplasms/genetics , MicroRNAs/genetics , RNA Processing, Post-Transcriptional/genetics , Tumor Suppressor Proteins/genetics
9.
Braz. j. med. biol. res ; 47(1): 42-49, 01/2014. tab, graf
Article in English | LILACS | ID: lil-697672

ABSTRACT

Membranous nephropathy (MN), characterized by the presence of diffuse thickening of the glomerular basement membrane and subepithelial in situ immune complex disposition, is the most common cause of idiopathic nephrotic syndrome in adults, with an incidence of 5-10 per million per year. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of human MN, but the specific biomarkers of MN have not been fully elucidated. As a result, our knowledge of the alterations in histone methylation in MN is unclear. We used chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to analyze the variations in a methylated histone (H3K9me3) in peripheral blood mononuclear cells from 10 MN patients and 10 healthy subjects. There were 108 genes with significantly different expression in the MN patients compared with the normal controls. In MN patients, significantly increased activity was seen in 75 H3K9me3 genes, and decreased activity was seen in 33, compared with healthy subjects. Five positive genes, DiGeorge syndrome critical region gene 6 (DGCR6), sorting nexin 16 (SNX16), contactin 4 (CNTN4), baculoviral IAP repeat containing 3 (BIRC3), and baculoviral IAP repeat containing 2 (BIRC2), were selected and quantified. There were alterations of H3K9me3 in MN patients. These may be candidates to help explain pathogenesis in MN patients. Such novel findings show that H3K9me3 may be a potential biomarker or promising target for epigenetic-based MN therapies.


Subject(s)
Adult , Female , Humans , Male , Glomerulonephritis, Membranous/genetics , Histones/genetics , Leukocytes, Mononuclear/metabolism , Lysine/genetics , Case-Control Studies , Chromatin Immunoprecipitation , Glomerulonephritis, Membranous/metabolism , Histones/metabolism , Lysine/metabolism , Methylation
10.
Yonsei Medical Journal ; : 1333-1340, 2014.
Article in English | WPRIM | ID: wpr-210325

ABSTRACT

PURPOSE: The aim of this work was to evaluate nuclear histone acetylation level and total histone acetyltransferase (HAT) and deacetylase (HDAC) activity in ejaculated sperm and their relevance to conventional sperm parameters. MATERIALS AND METHODS: Thirty-three normozoospermic men were included in this study. Semen samples were processed by swim-up and then immunostained by six acetylation antibodies (H3K9ac, H3K14ac, H4K5ac, H4K8ac, H4K12ac, and H4K16ac). Our preliminary study verified the expression of HAT/HDAC1 in mature human sperm. From vitrified-warmed sperm samples, total HAT/HDAC activity was measured by commercially available kits. Nuclear DNA integrity was also measured by TUNEL assay. RESULTS: The levels of six acetylation marks were not related with conventional sperm parameters including sperm DNA fragmentation index (DFI) as well as HAT/HDAC activity. However, sperm DFI was positively correlated with HAT activity (r=0.038 after adjustment, p<0.02). HAT activity showed a negative relationship with HDAC activity (r=-0.51, p<0.01). Strict morphology was negatively correlated with acetylation enzyme index (=HAT activity/HDAC activity) (r=-0.53, p<0.01). CONCLUSION: Our works demonstrated a significant relationship of acetylation-associated enzyme activity and strict morphology or sperm DFI.


Subject(s)
Acetylation , Adult , DNA Fragmentation , Epigenesis, Genetic , Histone Acetyltransferases/metabolism , Histones/metabolism , Humans , Immunohistochemistry , Male , Middle Aged , Protein Processing, Post-Translational , Semen Analysis , Spermatozoa/metabolism
11.
Article in English | WPRIM | ID: wpr-163227

ABSTRACT

Histone deacetylases are involved in many biological processes and have roles in regulating cell behaviors such as cell cycle entry, cell proliferation and apoptosis. However, the effect of histone deacetylases on the development of hair cells (HCs) has not been fully elucidated. In this study, we examined the influence of histone deacetylases on the early development of neuromasts in the lateral line of zebrafish. Hair cell development was evaluated by fluorescent immunostaining in the absence or presence of histone deacetylase inhibitors. Our results suggested that pharmacological inhibition of histone deacetylases with inhibitors, including trichostatin A, valproic acid and MS-275, reduced the numbers of both HCs and supporting cells in neuromasts. We also found that the treatment of zebrafish larvae with inhibitors caused accumulation of histone acetylation and suppressed proliferation of neuromast cells. Real-time PCR results showed that the expression of both p21 and p27 mRNA was increased following trichostatin A treatment and the increase in p53 mRNA was modest under the same conditions. However, the expression of p53 mRNA was significantly increased by treatment with a high concentration of trichostatin A. A high concentration of trichostatin A also led to increased cell death in neuromasts as detected in a TUNEL assay. Moreover, the nuclei of most of these pyknotic cells were immunohistochemically positive for cleaved caspase-3. These results suggest that histone deacetylase activity is involved in lateral line development in the zebrafish and might have a role in neuromast formation by altering cell proliferation through the expression of cell cycle regulatory proteins.


Subject(s)
Animals , Apoptosis , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor Proteins/genetics , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Histones/metabolism , Larva/growth & development , Lateral Line System/cytology , Mechanoreceptors/drug effects , RNA, Messenger/genetics , Zebrafish , Zebrafish Proteins/metabolism
12.
Mem. Inst. Oswaldo Cruz ; 107(supl.1): 174-182, Dec. 2012. ilus, graf
Article in English | LILACS | ID: lil-659756

ABSTRACT

When grown in the presence of exogenous collagen I, Mycobacterium bovis BCG was shown to form clumps. Scanning electron microscopy examination of these clumps revealed the presence of collagen fibres cross-linking the bacilli. Since collagen is a major constituent of the eukaryotic extracellular matrices, we assayed BCG cytoadherence in the presence of exogenous collagen I. Collagen increased the interaction of the bacilli with A549 type II pneumocytes or U937 macrophages, suggesting that BCG is able to recruit collagen to facilitate its attachment to host cells. Using an affinity chromatography approach, we have isolated a BCG collagen-binding protein corresponding to the previously described mycobacterial laminin-binding histone-like protein (LBP/Hlp), a highly conserved protein associated with the mycobacterial cell wall. Moreover, Mycobacterium leprae LBP/Hlp, a well-characterized adhesin, was also able to bind collagen I. Finally, using recombinant fragments of M. leprae LBP/Hlp, we mapped the collagen-binding activity within the C-terminal domain of the adhesin. Since this protein was already shown to be involved in the recognition of laminin and heparan sulphate-containing proteoglycans, the present observations reinforce the adhesive activities of LBP/Hlp, which can be therefore considered as a multifaceted mycobacterial adhesin, playing an important role in both leprosy and tuberculosis pathogenesis.


Subject(s)
Animals , Humans , Bacterial Adhesion , Collagen Type I/pharmacology , Mycobacterium bovis/metabolism , Mycobacterium leprae/metabolism , Bacterial Adhesion/immunology , Carrier Proteins/immunology , Carrier Proteins/metabolism , Collagen Type I/metabolism , Histones/metabolism , Mycobacterium bovis/immunology , Mycobacterium leprae/immunology
13.
Yonsei Medical Journal ; : 377-385, 2012.
Article in English | WPRIM | ID: wpr-154804

ABSTRACT

PURPOSE: The purpose of the present study was to investigate the aberrance of histone H3 lysine 4 trimethylation (H3K4me3) in patients with IgA Nephropathy (IgAN). MATERIALS AND METHODS: In this study, H3K4me3 variations in peripheral blood mononuclear cells (PBMCs) from 15 IgAN patients and 15 healthy subjects were analyzed using chromatin immunoprecipitation linked to microarrays analysis (ChIP-chip). ChIP real-time PCR was used to validate the microarray results. Expression analysis by quantitative real-time PCR (qRT-PCR) revealed correlations between mRNA and H3K4me3 levels. DNA methylation status was analyzed by quantitative methylation-specific PCR. RESULTS: We found that 321 probes displayed significant H3K4me3 differences in IgAN patients compared with healthy controls. Among these probes, 154 probes displayed increased H3K4me3 and 167 probes demonstrated decreased H3K4me3. For further validation, we selected 4 key relevant genes (FCRL4, GALK2, PTPRN2 and IL1RAPL1) to study. The results of ChIP real-time PCR coincided well with the microarray data. Quantitative RT-PCR revealed the correlations between the mRNA expression and the methylation levels of H3K4me3. Different degrees of DNA methylation alterations appeared on the selected positive genes. CONCLUSION: Our studies indicated that there were significant alterations in H3K4me3 in IgAN patients. These findings may help to explain the disturbed immunity and abnormal glycosylation involved in IgAN patients.


Subject(s)
Adult , Case-Control Studies , Chromatin Immunoprecipitation , Female , Glomerulonephritis, IGA/genetics , Histones/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Lysine/metabolism , Male , Methylation , Oligonucleotide Array Sequence Analysis/methods , Real-Time Polymerase Chain Reaction , Young Adult
14.
Article in Korean | WPRIM | ID: wpr-194407

ABSTRACT

BACKGROUND/AIMS: DNA double strand break (DSB) is one of the critical types of DNA damage. When unrepaired DSB is accumulated in the nucleus of the cells having mutations in such genes as p53, it will lead to chromosomal instability and further more to mutation of tumor-activating genes resulting in tumorogenesis. Some of malignant cancers and its premalignant lesions were proven to have DSB in their nuclei. The aim of this study was to define the differences in expression of 53BP1 and gamma-H2AX, the markers of DSB, among normal, gastric adenoma, and gastric adenocarcinoma tissues. METHODS: Tissue microarray was made with the tissues taken from 121 patients who underwent gastrectomy for gastric adenocarcinoma, and 51 patients who underwent endoscopic mucosal resection for gastric adenoma. Immunochemical stain was performed for the marker of DSB, 53BP1 and gamma-H2AX in the tissue microarray. The normal tissues were collected from histologically confirmed tissues with no cellular atypia obtained from the patients with gastric adenocarcinoma. RESULTS: In gastric carcinoma cells, 53BP1 and gamma-H2AX were highly expressed as compared to normal epithelial cells and gastric adenoma (p<0.01). There were no differences in the expression of 53BP1 and gamma-H2AX between normal epithelium and gastric adenoma. The expression of 53BP1 in the adenoma with grade II and III atypism was more elevated than in those with grade I atypism. The expression of 53BP1 and gamma-H2AX were not significantly different according to the clinicopathologic parameters in the patients with gastric adenocarcinoma. CONCLUSIONS: The DSB in DNA seems to be associated with the development of gastric adenocarcinoma, but does not affect the premalignant adenoma cells.


Subject(s)
Adenocarcinoma/genetics , Adenoma/genetics , Adult , Aged , Aged, 80 and over , Chromosomal Instability , DNA Breaks, Double-Stranded , Female , Histones/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Male , Middle Aged , Neoplasm Staging , Stomach Neoplasms/genetics
15.
Article in English | WPRIM | ID: wpr-214630

ABSTRACT

Epigenomic and genomic changes affect gene expression and contribute to tumor development. The histone modifications trimethylated histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) are epigenetic regulators associated to active and silenced genes, respectively and alterations of these modifications have been observed in cancer. Furthermore, genomic aberrations such as DNA copy number changes are common events in tumors. Pheochromocytoma is a rare endocrine tumor of the adrenal gland that mostly occurs sporadic with unknown epigenetic/genetic cause. The majority of cases are benign. Here we aimed to combine the genome-wide profiling of H3K4me3 and H3K27me3, obtained by the ChIP-chip methodology, and DNA copy number data with global gene expression examination in a malignant pheochromocytoma sample. The integrated analysis of the tumor expression levels, in relation to normal adrenal medulla, indicated that either histone modifications or chromosomal alterations, or both, have great impact on the expression of a substantial fraction of the genes in the investigated sample. Candidate tumor suppressor genes identified with decreased expression, a H3K27me3 mark and/or in regions of deletion were for instance TGIF1, DSC3, TNFRSF10B, RASSF2, HOXA9, PTPRE and CDH11. More genes were found with increased expression, a H3K4me3 mark, and/or in regions of gain. Potential oncogenes detected among those were GNAS, INSM1, DOK5, ETV1, RET, NTRK1, IGF2, and the H3K27 trimethylase gene EZH2. Our approach to associate histone methylations and DNA copy number changes to gene expression revealed apparent impact on global gene transcription, and enabled the identification of candidate tumor genes for further exploration.


Subject(s)
Adrenal Gland Neoplasms/genetics , Epigenesis, Genetic , Female , Gene Dosage/genetics , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks/genetics , Genome, Human/genetics , Genomics , Histones/metabolism , Humans , Lysine/metabolism , Methylation , Pheochromocytoma/genetics , Protein Processing, Post-Translational , Tumor Suppressor Proteins/genetics
16.
Biol. Res ; 42(4): 445-460, 2009. ilus, graf
Article in English | LILACS | ID: lil-537104

ABSTRACT

Although several histone variants have been studied in both animal and plant organisms, little is known about their distribution during processes that involve alterations in chromatin function, such as differentiation, dedifferentiation and hormone treatment. In this study we evaluated the ratio of each histone variant in each of the four core histone classes in the three developmental zones of maize (Zea mays L.) root and in callus cultures derived from them, in order to define possible alterations either during plant cell differentiation or dedifferentiation. We also evaluated core histone variant ratios in the developmental zones of roots treated with auxin and gibberellin in order to examine the effects of exogenously applied plant hormones to histone variant distribution. Finally, immunohistochemical detection was used to identify the root tissues containing modified forms of core histones and correlates them with the physiological status of the plant cells. According to the results presented in this study, histone variant ratios are altered in all the cases examined, i.e. in the developmental zones of maize root, in callus cultures derived from them and in the developmental zones of roots treated either with auxin or gibberellin. We propose that the alterations in linker histone variant ratios are correlated with plant cell differentiation and physiological status in each case.


Subject(s)
Histones/metabolism , Plant Growth Regulators/pharmacology , Plant Roots/embryology , Zea mays/embryology , Blotting, Western , Cell Differentiation , Densitometry , Gibberellins , Histones/classification , Immunohistochemistry , Indoleacetic Acids , Plant Growth Regulators/isolation & purification , Plant Roots/chemistry , Plant Roots/drug effects , Zea mays/chemistry , Zea mays/drug effects
17.
Yonsei Medical Journal ; : 455-463, 2009.
Article in English | WPRIM | ID: wpr-143691

ABSTRACT

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.


Subject(s)
DNA Methylation/physiology , Epigenesis, Genetic/physiology , Histone-Lysine N-Methyltransferase/metabolism , Histones/metabolism , Humans , Models, Biological , Neoplasms/genetics
18.
Yonsei Medical Journal ; : 455-463, 2009.
Article in English | WPRIM | ID: wpr-143682

ABSTRACT

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.


Subject(s)
DNA Methylation/physiology , Epigenesis, Genetic/physiology , Histone-Lysine N-Methyltransferase/metabolism , Histones/metabolism , Humans , Models, Biological , Neoplasms/genetics
19.
Article in English | WPRIM | ID: wpr-136595

ABSTRACT

Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)beta, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRalpha. However, recent data suggest that GRbeta is not a dominant negative inhibitor of GRalpha in the transrepressive process and has its own functional role. We investigated the functional role of GRbeta expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-alpha-induced IL-8 release in an airway epithelial cell line. GRbeta expression was induced by treatment of epithelial cells with either dexamethasone or TNF-alpha. GRbeta was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-alpha-induced IL-8 transcription was not affected by GRbeta overexpression, rather GRbeta had its own weak suppressive activity on TNF-alpha-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRbeta overexpression, but TNF-alpha-induced histone H4 acetylation at the IL-8 promoter was decreased with GRbeta overexpression. This study suggests that GRbeta overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRbeta induces its own histone deacetylase activity around IL-8 promoter site.


Subject(s)
Acetylation , Cell Line, Tumor , Dexamethasone/pharmacology , Epithelial Cells/metabolism , Gene Expression Regulation , Histones/metabolism , Humans , Interleukin-8/genetics , Receptors, Glucocorticoid/genetics , Transcriptional Activation , Transfection , Tumor Necrosis Factor-alpha/antagonists & inhibitors
20.
Article in English | WPRIM | ID: wpr-136594

ABSTRACT

Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)beta, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRalpha. However, recent data suggest that GRbeta is not a dominant negative inhibitor of GRalpha in the transrepressive process and has its own functional role. We investigated the functional role of GRbeta expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-alpha-induced IL-8 release in an airway epithelial cell line. GRbeta expression was induced by treatment of epithelial cells with either dexamethasone or TNF-alpha. GRbeta was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-alpha-induced IL-8 transcription was not affected by GRbeta overexpression, rather GRbeta had its own weak suppressive activity on TNF-alpha-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRbeta overexpression, but TNF-alpha-induced histone H4 acetylation at the IL-8 promoter was decreased with GRbeta overexpression. This study suggests that GRbeta overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRbeta induces its own histone deacetylase activity around IL-8 promoter site.


Subject(s)
Acetylation , Cell Line, Tumor , Dexamethasone/pharmacology , Epithelial Cells/metabolism , Gene Expression Regulation , Histones/metabolism , Humans , Interleukin-8/genetics , Receptors, Glucocorticoid/genetics , Transcriptional Activation , Transfection , Tumor Necrosis Factor-alpha/antagonists & inhibitors
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