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1.
Adv Exp Med Biol ; 1164: 179-196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576549

RESUMO

DNA methylation is a chemically reversible epigenetic modification that regulates the chromatin structure and gene expression, and thereby takes part in various cellular processes like embryogenesis, genomic imprinting, X-chromosome inactivation, and genome stability. Alterations in the normal methylation levels of DNA may contribute to the development of pathological conditions like cancer. Even though both hypo- and hypermethylation-mediated abnormalities are prevalent in the cancer genome, the field of cancer epigenetics has been more focused on targeting hypermethylation. As a result, DNA hypomethylation-mediated abnormalities remained relatively less explored, and currently, there are no approved drugs that can be clinically used to target hypomethylation. Understanding the precise role of DNA hypomethylation is not only crucial from a mechanistic point of view but also for the development of pharmacological agents that can reverse the hypomethylated state of the DNA. This chapter focuses on the causes and impact of DNA hypomethylation in the development of cancer and describes the possible ways to pharmacologically target it, especially by using a naturally occurring physiologic agent S-adenosylmethionine (SAM).


Assuntos
Metilação de DNA , Epigênese Genética , Neoplasias , Epigenômica , Humanos , Neoplasias/genética , Neoplasias/terapia
2.
Anticancer Res ; 39(10): 5361-5367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570430

RESUMO

BACKGROUND/AIM: The mechanism responsible for B-cell translocation gene 1 (BTG1) down-regulation in breast carcinoma remains unknown. We examined the BTG1 expression status in breast carcinoma cells and investigated the mechanism underlying the observed alterations. MATERIALS AND METHODS: Four breast carcinoma cell lines (SK-BR-3, MDA-MB-231, T-47D, and MCF-7), and one normal mammary epithelial cell line (MCF-10A) were analyzed. BTG1 expression was examined using quantitative reverse transcription polymerase chain reaction (PCR) and western blot. Methylation status of the BTG1 promoter was analyzed using methylation-specific PCR (MSP). To investigate the effect of methylation on BTG1, the cells were treated with a demethylating agent. RESULTS: The carcinoma cells expressed significantly lower levels of BTG1 mRNA and protein than normal cells. The BTG1 promoter was highly methylated in the carcinoma cells. 5-aza-2-deoxycytidine significantly restored BTG1 expression. CONCLUSION: Down-regulation of BTG1 expression through epigenetic repression is involved in mammary carcinogenesis. BTG1 is a potential diagnostic marker and therapeutic target for breast carcinoma.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA/genética , Regulação para Baixo/genética , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , RNA Mensageiro/genética
3.
Anticancer Res ; 39(10): 5473-5481, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570441

RESUMO

BACKGROUND/AIM: Aerial parts and seeds of the neem tree (Azadirachta indica) have long been used in traditional medicine such as Ayurveda for health-related purposes. Our interest in neem bioactives lies in their potential use as standalone anticancer agents, or as adjuvants to standard therapy. The aim of the present study was to explore a supercritical CO2 extract (SCNE) of neem leaf and a prominent liminoid in neem leaf, nimbolide, for epigenetic activity. MATERIALS AND METHODS: Human colorectal cancer cell lines (HCT116 and HT29) were cultured for 48 h in the presence of neem extract or nimbolide and evaluated for growth inhibition and evidence of suppression of histone deacetylation and DNA methylation. RESULTS: Both SCNE and nimbolide suppressed the proliferation of colon cancer cells by inducing epigenetic modifications. CONCLUSION: Neem leaf contains bioactive constituents which modify epigenetic activity.


Assuntos
Azadirachta/química , Neoplasias Colorretais/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Dióxido de Carbono/química , Dióxido de Carbono/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Limoninas/farmacologia
4.
Anticancer Res ; 39(10): 5573-5579, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570452

RESUMO

BACKGROUND/AIM: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, frequently infected with Merkel cell polyomavirus (MCPyV). H3K27me3 acts as a repressive histone modification that epigenetically controls gene transcription. The aim of this study was to examine H3K27me3 expression in MCC. MATERIALS AND METHODS: H3K27me3 expression levels were immunohistochemically analyzed in 20 MCPyV-positive MCCs, 15 MCPyV-negative MCCs with squamous cell carcinoma (SCC) (combined MCCs), and six MCPyV-negative pure MCCs. RESULTS: Reduced H3K27me3 expression was variously observed in MCCs. H3K27me3 H-score was significantly lower in MCPyV-negative MCCs than in MCPyV-positive MCCs (p=0.002). H3K27me3 expression was significantly lower in MCPyV-negative combined MCC component than in MCPyV-positive MCCs (p<0.001), MCPyV-negative pure MCCs (p=0.036), or pure MCC histology (p<0.001). Kaplan-Meier analysis showed no association of H3K27me3 with outcome. CONCLUSION: Differential reduction in H3K27me3 expression was observed based on MCPyV status and morphological type. These results implicate H3K27me3-mediated epigenetic changes in tumorigenesis of MCC, especially in MCPyV-negative MCC combined with SCC.


Assuntos
Carcinoma de Célula de Merkel/genética , Carcinoma de Células Escamosas/genética , Histonas/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinoma de Célula de Merkel/virologia , Carcinoma de Células Escamosas/virologia , Epigênese Genética/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Poliomavírus das Células de Merkel/patogenicidade , Pessoa de Meia-Idade , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/virologia , Neoplasias Cutâneas/virologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/virologia
5.
Exp Suppl ; 111: 3-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588524

RESUMO

Genetics is the study of heredity. In this introductory chapter of the book Genetics of Endocrine Diseases and Syndromes, we present the basic terms of genetics and basic physiological and pathogenic molecular processes that are implicated in the wide array of genetically determined diseases. Mutations, chromosomes, polymorphisms, and epigenetic terms are also briefly discussed.


Assuntos
Cromossomos Humanos/genética , Doenças do Sistema Endócrino/genética , Hereditariedade , Polimorfismo Genético , Epigênese Genética , Humanos , Mutação
6.
Adv Exp Med Biol ; 1167: 105-112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31520351

RESUMO

Human P53 (HsP53) is the most frequently mutated gene associated with cancers. Despite heightened research interest over the last four decades, a clear picture of how wild type HsP53 functions as the guardian against malignant transformation remains elusive. Studying the ortholog of P53 in the genetic model organism Drosophila melanogaster (DmP53) has revealed many interesting insights. This chapter focuses on recent findings that have shed light on how DmP53 -mediated apoptosis plays an important role in maintaining genome integrity, and how the immediate output of activated DmP53 is determined by the epigenetic landscape of individual cells.


Assuntos
Apoptose , Proteínas de Drosophila/genética , Drosophila melanogaster , Proteína Supressora de Tumor p53/genética , Animais , Epigênese Genética , Instabilidade Genômica , Humanos
7.
Nihon Yakurigaku Zasshi ; 154(3): 108-113, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31527359

RESUMO

Similar to calcium (Ca2+) and chloride (Cl-) ion channels/transporters, potassium (K+) channels have been recognized as a crucial cancer treatment target. Recent studies have provided convincing evidences of positive correlation between elevated expression levels of Ca2+-activated K+ (KCa) channels and cancer proliferation, metastasis, and poor patient prognosis. In cancer cells, KCa1.1 and KCa3.1 KCa channels are co-localized with Ca2+-permeable Orai/TRP channels to provide a positive-feedback loop for Ca2+ entry. They are responsible for the promotion of cell growth and metastasis in the different types of cancer, and are therefore potential therapeutic targets and biomarkers for cancer. We determined the epigenetic and post-transcriptional dysregulation of KCa3.1 by class I histone deacetylase inhibitors in breast and prostate cancer cells. We further determined the transcriptional repression and protein degradation of KCa1.1 by vitamin D receptor agonists and androgen receptor antagonists, which are expected as potential therapeutic drugs for triple-negative breast cancer. The anti-inflammatory cytokine, interleukin-10 (IL-10) is an immunosuppressive factor involved in tumorigenesis, and plays a crucial role in escape from tumor immune surveillance. We determined KCa3.1 activators are a possible therapeutic option to suppress the tumor-promoting activities of IL-10. These results may provide new insights into cancer treatment focused on Ca2+-activated K+ channels.


Assuntos
Neoplasias da Mama/patologia , Inibidores de Histona Desacetilases/farmacologia , Canais de Potássio Cálcio-Ativados/metabolismo , Neoplasias da Próstata/patologia , Antagonistas de Receptores de Andrógenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Epigênese Genética , Feminino , Humanos , Vigilância Imunológica , Interleucina-10/metabolismo , Masculino , Proteólise , Processamento Pós-Transcricional do RNA , Receptores de Calcitriol/agonistas
8.
Adv Exp Med Biol ; 1178: 175-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31493228

RESUMO

A global DNA hypomethylation and local changes in the methylation levels of specific DNA loci occur during aging in mammals. Global hypomethylation mainly affects highly methylated repeat sequences, such as transposable elements; it is an essentially stochastic process usually referred to as "epigenetic drift." Specific changes in DNA methylation affect various genome sequences and could be either hypomethylation or hypermethylation, but the prevailing tendencies are hypermethylation of promoter sequences associated with CpG islands and hypomethylation of CpG poor genes. Methylation levels of multiple CpG sites display a strong correlation to age common between individuals of the same species. Collectively, methylation of such CpG sites could be used as "epigenetic clocks" to predict biological age. Furthermore, the discrepancy between epigenetic and chronological ages could be predictive of all-cause mortality and multiple age-associated diseases. Random changes in DNA methylation (epigenetic drift) could also affect the aging phenotype, causing accidental changes in gene expression and increasing the transcriptional noise between cells of the same tissue. Both effects could become detrimental to tissue functioning and cause a gradual decline in organ function during aging. Strong evidence shows that epigenetic systems contribute to lifespan control in various organisms. Similar to other cell systems, the epigenome is prone to gradual degradation due to the genome damage, stressful agents and other aging factors. However, unlike mutations and many other hallmarks of aging, age-related epigenetic changes could be fully or partially reversed to a "young" state.


Assuntos
Envelhecimento , Epigênese Genética , Marcadores Genéticos , Envelhecimento/genética , Animais , Ilhas de CpG/genética , Metilação de DNA , Epigenômica , Marcadores Genéticos/genética , Longevidade
10.
Cancer Discov ; 9(9): 1158-1160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31481404

RESUMO

In this issue of Cancer Discovery, Gu and colleagues developed a mouse model of myeloproliferative neoplasm driven by Nras G12D and Ezh2-/- , which cooperated to induce malignant transformation and metabolic reprogramming of leukemic stem cells at least in part through loss of normal epigenetic regulation of gene expression. Furthermore, their findings point to Ezh1 and branched chain amino acid metabolism as biological dependencies and potential therapeutic targets in myeloid neoplasms.See related article by Gu et al., p. 1228.


Assuntos
Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Animais , Transformação Celular Neoplásica/genética , Epigênese Genética , Camundongos , Células-Tronco
11.
Cancer Discov ; 9(9): 1161-1163, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31481405

RESUMO

In this issue of Cancer Discovery, Gimple and colleagues examine superenhancers in glioblastoma and glioma stem cells (GSC), identifying one which promotes expression of ELOVL2, an enzyme in polyunsaturated fatty acid (PUFA) synthesis. They find that ELOVL2 products help maintain cell membrane organization and EGFR signaling in GSCs, and that targeting PUFA metabolism along with EGFR offers a potential novel therapeutic strategy for glioblastoma.See related article by Gimple et al., p. 1248.


Assuntos
Glioblastoma/genética , Glioma , Epigênese Genética , Receptores ErbB , Humanos , Células-Tronco Neoplásicas
12.
Ther Umsch ; 76(4): 173-178, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31498035

RESUMO

Current methods in molecular pathology Abstract. Macroscopy and microscopy were the cornerstones of tumor analysis in pathology for many years. Recently, we have witnessed an enormous increase in knowledge of genetic and epigenetic alterations occurring in tumors. The detection of these alterations is becoming increasingly important during pathological work-up because they have an important impact on the diagnosis, prognosis, therapy, and prevention of tumors. It is therefore crucial to have appropriate methods available to detect these genetic alterations, such as mutations, translocations or changes in the methylation profile. In the following review article, we will present current methods that are being applied in molecular pathology.


Assuntos
Neoplasias , Patologia Molecular , Epigênese Genética , Humanos , Prognóstico
15.
Adv Exp Med Biol ; 1200: 71-89, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471795

RESUMO

The ability to adapt to changing environmental conditions is critical for any species to survive. Many environmental changes occur too rapidly for an organism's genome to adapt in time. Accordingly, being able to modify either its own phenotype, or the phenotype of its offspring to better suit future anticipated environmental conditions could afford an organism a significant advantage. However, a range of animal models and human epidemiological data sets are now showing that environmental factors such as changes in the quality or quantity of an individual's diet, temperature, stress or exposure to pollutants can all adversely affect the quality of parental gametes, the development of the preimplantation embryo and the health and wellbeing of offspring over multiple generations. This chapter will examine transgenerational effects of both maternal and paternal environmental factors on offspring development and wellbeing in both human and animal model studies. Changes in the epigenetic status of either parental or grand-parental gametes provide one candidate mechanism through which the impacts of environmental experience can be passed from one generation to another. This chapter will therefore also focus on the impact of parental and grand-parental diet on epigenetic transgenerational inheritance and offspring phenotype.


Assuntos
Adaptação Biológica/genética , Dieta , Meio Ambiente , Epigênese Genética , Animais , Humanos , Modelos Animais , Fenótipo
16.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 548-555, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484620

RESUMO

Leukemia is a disease featured by the malignant proliferation of hematopoietic stem cells or progenitor cells in the blood system.While chemotherapy remains its mainstream treatment,disease relapse and drug resistance are still challenging problems.As one of the epigenetic mechanisms,histone methylation is involved in cell proliferation,differentiation,and apoptosis by regulating gene transcription.Recent studies have found that the histone demethylase lysine-specific demethylase 6A(KDM6A),also known as ubiquitously transcribed tetratricopeptide repeat on chromosome X(UTX),is closely related to the occurrence of a variety of tumors,especially leukemia.KDM6A activates gene expression by demethylating H3K27me3 to H3K27me2 or H3K27me1.Besides,KDM6A can regulate the activation of the target gene transcription through its non-demethylase functions.It can serve as the subunit of complex of proteins associated with Set1,thus getting involved in the regulation of H3K4me1.It can be combined with yeast mating type conversion/sucrose unfermented complex family to promote the formation of an open chromatin conformation.Finally,it can promote the production of H3K27ac.This article reviews the recent studies on the structure and biological activity of histone demethylase KDM6A(UTX)and its role in treating leukemia,thus providing a new research direction for targeted treatment of leukemia.


Assuntos
Epigênese Genética , Histona Desmetilases/metabolismo , Leucemia/enzimologia , Lisina , Proteínas Nucleares/metabolismo , Histonas , Humanos , Leucemia/terapia
17.
Adv Exp Med Biol ; 1152: 293-310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456191

RESUMO

Epigenetics refers to alterations in gene expression due to differential histone modifications and DNA methylation at promoter sites of genes. Epigenetic alterations are reversible and are heritable during somatic cell division, but do not involve changes in nucleotide sequence. Epigenetic regulation plays a critical role in normal growth and embryonic development by controlling transcriptional activities of several genes. In last two decades, these modifications have been well recognized to be involved in tumor initiation and progression, which has motivated many investigators to incorporate this novel field in cancer drug development. Recently, growing number of epigenetic changes have been reported that are involved in the regulations of genes involved in breast tumor growth and metastasis. Drugs possessing epigenetic modulatory activities known as epi-drugs, mainly the inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Some of these drugs are undergoing different clinical trials for breast cancer treatment. Several phytochemicals such as green tea polyphenols, curcumin, genistein, resveratrol and sulforaphane have also been shown to alter epigenetic modifications in multiple cancer types including breast cancer. In this chapter, we summarize the role of epigenetic changes in breast cancer progression and metastasis. We have also discussed about various epigenetic modulators possessing chemopreventive and therapeutic efficacy against breast cancer with future perspectives.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Epigênese Genética , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Metilação de DNA , Feminino , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases , Humanos , Compostos Fitoquímicos/farmacologia
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(7): 830-836, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31413224

RESUMO

Colorectal cancer is one of the common malignant tumors, which seriously threatens human health. Its morbidity and mortality rank the third and the second among all malignant tumors. The progress of colorectal cancer is a complex process involving the accumulation of genetic and epigenetic changes. Epigenetic changes of colorectal cancer mainly include DNA methylation, histone modification, non-coding RNAs (such as microRNAs and lncRNAs), which are of great significance to early diagnosis and prognosis evaluation, and to chemosensitivity assessment for colorectal cancer, providing a new thought for the treatment of colorectal cancer.


Assuntos
Neoplasias Colorretais , Epigênese Genética , Neoplasias Colorretais/genética , Metilação de DNA , Epigenômica , Histonas , Humanos
19.
Adv Exp Med Biol ; 1121: 7-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392648

RESUMO

Common Non communicable diseases (NCDs), such as cardiovascular disease, cancer, schizophrenia, and diabetes, have become the major cause of death in the world. They result from an interaction between genetics, lifestyle and environmental factors. The prevalence of NCDs are increasing, and researchers hopes to find efficient strategies to predict, prevent and treat them. Given the role of epigenome in the etiology of NCDs, insight into epigenetic mechanisms may offer opportunities to predict, detect, and prevent disease long before its clinical onset.Epigenetic alterations are exerted through several mechanisms including: chromatin modification, DNA methylation and controlling gene expression by non-coding RNAs (ncRNAs). In this chapter, we will discuss about NCDs, with focus on cancer, diabetes and schizophrenia. Different epigenetic mechanisms, categorized into two main groups DNA methylation and chromatin modifications and non-coding RNAs, will be separately discussed for these NCDs.


Assuntos
Epigênese Genética , Doenças não Transmissíveis , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Humanos , Neoplasias/genética , Esquizofrenia/genética
20.
Toxicol Lett ; 315: 31-38, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419471

RESUMO

Endocrine disruptor zearalenone (ZEA) has been found to damage the reproductive system especially spermatogenesis. In our previous report, we have found that low dose (lower than No-Observed Effect Level, NOEL) ZEA exposure disturbed mouse spermatogenesis and diminished mouse semen quality. The purpose of current investigation was to explore the underlying mechanisms of pubertal low dose ZEA exposure upsetting spermatogenesis. And it was demonstrated that pubertal low dose ZEA exposure disrupted the meiosis process and the important genetic pathways to inhibit the spermatogenesis and even to diminish the semen quality with the decrease in spermatozoa motility and concentration. The DNA methylation markers 5mC and 5hmC were decreased, the histone methylation marker H3K27 was increased, at the same time estrogen receptor alpha was diminished in mouse testis after pubertal low dose ZEA exposure. The data indicate that the disruption in spermatogenesis by pubertal low dose ZEA exposure may be through the alterations in genetic and epigenetic pathways, and the interactions with estrogen receptor signaling pathway. Therefore, we should pay great attention on ZEA exposure to reduce its adverse impacts on male reproductive health.


Assuntos
Divisão Celular/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Receptor alfa de Estrogênio/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Zearalenona/toxicidade , Adolescente , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos
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