Дисертації з теми "Prostate cancer; epigenetic modification"
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Mohamed, M. "Epigenetic biomarkers in prostate cancer." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426926.
Повний текст джерелаZhang, Qunshu. "Epigenetic Regulation of Apoptosis in Prostate Cancer." Diss., North Dakota State University, 2015. https://hdl.handle.net/10365/27614.
Повний текст джерелаChinaranagari, Swathi. "Epigenetic Silencing of ID4 in Prostate Cancer: Mechanistic Insight." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2015. http://digitalcommons.auctr.edu/cauetds/13.
Повний текст джерелаTaurozzi, Alberto. "Genetic and epigenetic profiling of human prostate cancer cell subsets." Thesis, University of York, 2016. http://etheses.whiterose.ac.uk/17511/.
Повний текст джерелаRibarska, Teodora [Verfasser]. "Expression and epigenetic regulation of imprinted genes in prostate cancer / Teodora Ribarska." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2013. http://d-nb.info/1036727513/34.
Повний текст джерелаKadio, Bernard. "A Calcium-Centered Socio-Ecological Model of Prostate Cancer Disparities: Preliminary Studies and Findings." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40685.
Повний текст джерелаGupta, Yukti Hari. "An investigation into BORIS expression in prostate cancer cells and its role in epigenetic regulation of the androgen receptor gene." Thesis, University of Essex, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.635911.
Повний текст джерелаWu, Mengchu. "The Epigenetic Silencing of PMP24 During the Progression of Prostate Cancer from an Androgen-Dependent to Androgen-Independent State in the LNCAP Cell Model: a Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/209.
Повний текст джерелаSiouda, Maha. "Transcriptional regulation and epigenetic repression of the tumor suppressor DOK1 in viral- and non viral-related carcinogenesis." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10163.
Повний текст джерелаThe newly identified tumor suppressor DOK1 (downstream of tyrosine kinases1) inhibits cell proliferation, negatively regulates MAP kinase activity, opposes leukemogenesis, and promotes cell spreading, motility, and apoptosis. DOK1 also plays a role in the regulation of immune cell activation, including B cells. The tumor suppressor role of DOK1 was demonstrated in animal models. DOK1 knockout mice show a high susceptibility to develop leukemia, hematological malignancies as well as lung adenocarcinomas and aggressive histiocytic sarcoma. In addition, we previously reported that the DOK1 gene can be mutated and its expression is down-regulated in human malignancies such as Burkitt’s lymphoma cell lines (BL) and chronic lymphocytic leukemia (CLL). However, very little is known about the mechanisms underlying DOK1 gene regulation and silencing in viral- and non viral-related tumorigenesis. In the present project, we first characterized the DOK1 promoter. We have shown the role of E2F1 transcription factor as the major regulator of DOK1 expression and how DOK1 plays a role in DNA stress response though opposing cell proliferation and promoting apoptosis. We demonstrated that DOK1 gene expression is repressed in a variety of human cancers, including head and neck, Burkitt’s lymphoma and lung cancers, as a result of aberrant hypermethylation. We investigated the link between the epigenetic events and DOK1 silencing in non viral head and neck cancer cell lines, and by Epstein Barr virus in relation to its oncogenic activity in human B cells and neoplasia such as Burkitt’s lymphoma. These data provide novel insights into the regulation of DOK1 in viral and non viral-related carcinogenesis, and could define it as a potential cancer biomarker and an attractive target for epigeneticbased therapy
Perriaud, Laury. "Étude systémique des cibles génomiques de la methyl-CpG binding domain protein 2 (MBD2), un répresseur transcriptionnel dépendant de la méthylation de l'ADN : évolution de la distribution de MBD2 dans un modèle syngénique de progression tumorale mammaire." Phd thesis, Université Claude Bernard - Lyon I, 2010. http://tel.archives-ouvertes.fr/tel-00833153.
Повний текст джерелаChiam, Karen HuiQin. "The role of epigenetic modifications in prostate tumourigenesis." Thesis, 2010. http://hdl.handle.net/2440/62617.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, School of Medicine, 2010
Martins, João Álvaro Barbosa. "Epigenetic regulation of micrornas in prostate cancer." Master's thesis, 2012. https://repositorio-aberto.up.pt/handle/10216/64998.
Повний текст джерелаMartins, João Álvaro Barbosa. "Epigenetic regulation of micrornas in prostate cancer." Dissertação, 2012. https://repositorio-aberto.up.pt/handle/10216/64998.
Повний текст джерелаGuan-RongLai and 賴冠榮. "Epigenetic Mechanisms of Vitamin D Resistance in Prostate Cancer." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/n7s53a.
Повний текст джерелаSantos, Pedro Alexandre Álvares Bargão dos. "Which epigenetic and inflammation related biomarkers can identify clinically aggressive prostate cancer." Doctoral thesis, 2020. http://hdl.handle.net/10362/105510.
Повний текст джерелаGraça, Maria Inês Pinho dos Santos. "Impact of epigenetic modulators on the malignant phenotype of prostate cancer cells." Doctoral thesis, 2014. https://repositorio-aberto.up.pt/handle/10216/84821.
Повний текст джерелаGraça, Maria Inês Pinho dos Santos. "Impact of epigenetic modulators on the malignant phenotype of prostate cancer cells." Tese, 2013. https://repositorio-aberto.up.pt/handle/10216/84821.
Повний текст джерела(9732323), Elena Wild. "Protein Arginine Methyltransferase 5 in Castration-Resistant and Neuroendocrine Prostate Cancer." Thesis, 2020.
Знайти повний текст джерелаIlic, Aleksandar. "Role of UCHL1 in regulating gene expression in prostate cancer cells." 2014. http://hdl.handle.net/1993/23912.
Повний текст джерелаOctober 2014
Lin, Tung-Yueh, and 林東岳. "Discovery and Modification of KDM4 Inhibitors in Castration-Resistant Prostate Cancer Treatment." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/zytbkf.
Повний текст джерелаSousa, Inês Margarida Marques de. "Genetic and epigenetic mechanisms involved in regulation of STEAP1 gene expression in LNCaP prostate cancer cells." Master's thesis, 2016. http://hdl.handle.net/10400.6/6289.
Повний текст джерелаO cancro da próstata é o segundo tipo de cancro mais frequentemente diagnosticado e a quinta principal causa de morte por cancro nos homens em todo o mundo. O desenvolvimento do cancro da próstata é caracterizado por alterações progressivas nos mecanismos genéticos e epigenéticos o que conduz a uma desregulação da expressão genética. O gene Six transmembrane epithelial antigen of the prostate 1 (STEAP1) codifica uma proteína com seis domínios transmembranares. Nos tecidos normais, a expressão do STEAP1 é muito baixa, no entanto é sobre-expresso em vários tipos de cancro nomeadamente no cancro da próstata. Vários estudos indicaram que a sobre-expressão do STEAP1 parece promover o crescimento celular, sugerindo que este pode actuar como um oncogene. Estudos anteriores demonstraram também que o mRNA e a proteína STEAP1 apresentam uma maior estabilidade em linhas celulares de cancro da próstata LNCaP quando comparado com as linhas celulares da próstata não-neoplásicas PNT1A. Esta diferença pode ser devida a modificações pós-transcricionais e/ou pós-translacionais. No entanto, estas alterações não justificam a sobre-expressão do STEAP1 em células tumorais, sugerindo assim o envolvimento de outros mecanismos de regulação. Portanto, o objectivo do presente trabalho foi explorar a hipótese de que alterações genéticas e/ou epigenéticas poderão estar envolvidas na sobre-expressão do STEAP1. A fim de avaliar a possível presença de alterações genéticas na sequência do gene STEAP1, foi sequenciada a região promotora do STEAP1 em células LNCaP e PNT1A. Para estudar o envolvimento de mecanismos epigenéticos, foram comparados os padrões de metilação do STEAP1 entre as linhas celulares PNT1A e LNCaP. Para além disso, foi ainda avaliado o efeito de um tratamento com inibidores das DNA metiltransferases (DNMT) e histonas desacetilases (HDAC) na expressão do gene STEAP1 em células PNT1A. A análise da sequência da região promotora do STEAP1 revelou algumas variantes tanto nas células LNCaP como PNT1A quando comparada com a sequência genómica disponível. A análise in silico das variantes mostrou diferenças nos fatores de transcrição que se podem ligar a cada variante alelica incluindo a ligação de activadores transcripcionais ao alelo alterado das variantes. A análise do padrão de metilação do STEAP1 entre células PNT1A e LNCaP mostrou diferenças na região promotora próxima do local de início da transcrição. O tratamento com 5-Aza-2’-deoxicitidina (inibidor das DNMT) induziu um ligeiro aumento na expressão do STEAP1 (três vezes em comparação com o grupo de controlo, p<0.01), enquanto que o tratamento com ambos os inibidores 5-Aza-2’-deoxicitidina e TSA (inibidor das HDAC) induziu um aumento acentuado na expressão do STEAP1 (quinze vezes relativamente ao grupo de controlo, p<0.001). A diferença no padrão de metilação do STEAP1 entre as células LNCaP e PNT1A, juntamente com o aumento da expressão do STEAP1 em resposta ao tratamento com os inibidores de HDACs e DNMTs, indica que a expressão génica do STEAP1 parece ser regulada por mecanismos epigenéticos.
"Modification of anticancer drug sensitivity of human prostate cancer cells by estrogen related compounds." 1998. http://library.cuhk.edu.hk/record=b5889640.
Повний текст джерелаThesis (M.Phil.)--Chinese University of Hong Kong, 1998.
Includes bibliographical references (leaves 117-123).
Abstract also in Chinese.
Acknowledgeements --- p.i
Abbreviations --- p.ii
Abstract --- p.v
List of Figures --- p.viii
List of Tables --- p.xiv
Contents --- p.xv
Contents
Chapter 1. --- Introduction --- p.1
Chapter 1.1 --- Epidemiological Risk Factors --- p.1
Chapter 1.1.1 --- Age --- p.1
Chapter 1.1.2 --- Race --- p.2
Chapter 1.1.3 --- Environmental or Migratory Factor --- p.2
Chapter 1.1.4 --- Diet --- p.2
Chapter 1.1.5 --- Genetics --- p.3
Chapter 1.2 --- Regulation of Normal Prostate Development and Function --- p.4
Chapter 1.3 --- Biochemistry and Development of Prostate Cancer --- p.6
Chapter 1.3.1 --- Androgen-Dependent Prostate Cancer --- p.6
Chapter 1.3.2 --- Androgen-Independent Prostate Cancer --- p.8
Chapter 1.4 --- Classification of Prostate Cancer --- p.9
Chapter 1.4.1 --- Stage A Prostate Cancer --- p.10
Chapter 1.4.2 --- Stage B Prostate Cancer --- p.10
Chapter 1.4.3 --- Stage C Prostate Cancer --- p.11
Chapter 1.4.4 --- Stage D Prostate Cancer --- p.11
Chapter 1.5 --- Methods for Early Detection of Prostate Cancer --- p.12
Chapter 1.6 --- Clinical Treatment of Prostate Cancer --- p.12
Chapter 1.6.1 --- Surgery --- p.12
Chapter 1.6.2 --- Radiotherapy --- p.13
Chapter 1.6.3 --- Chemotherapy --- p.13
Chapter 1.6.4 --- Hormonal Therapy --- p.13
Chapter 1.7 --- Objective --- p.14
Chapter 1.8 --- Estrogen and Its Related Compounds --- p.16
Chapter 1.8.1 --- 17β-Estradiol --- p.16
Chapter 1.8.2 --- Tamoxifen --- p.18
Chapter 1.8.3 --- Aromatase Inhibitor --- p.20
Chapter 1.9 --- Anticancer Drugs --- p.23
Chapter 1.9.1 --- Doxorubicin --- p.23
Chapter 1.9.2 --- cis-Platinum --- p.24
Chapter 1.10 --- Apoptotic Pathways --- p.25
Chapter 1.10.1 --- BCL-2 /BAD Pathway --- p.26
Chapter 1.10.2 --- FADD Pathway --- p.27
Chapter 1.10.3 --- CAS Pathway --- p.27
Chapter 2. --- Materials and Methods --- p.28
Chapter 2.1 --- Materials --- p.28
Chapter 2.2 --- Cell Lines --- p.32
Chapter 2.3 --- Preparation of Drugs --- p.32
Chapter 2.4 --- Drug Sensitivity Assay --- p.33
Chapter 2.5 --- Cell Cycle Analysis --- p.35
Chapter 2.6 --- DNA Fragmentation Assay --- p.36
Chapter 2.7 --- Annexin Binding Assay --- p.37
Chapter 2.8 --- Western Blot Analysis --- p.38
Chapter 2.9 --- Data Analysis --- p.41
Chapter 3. --- Results --- p.42
Chapter 3.1 --- Response of Human Androgen-Independent Prostate Cancer Cells to Doxorubicin and cis-Platinum --- p.42
Chapter 3.2 --- The Effect of 17p-Estradiol on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.45
Chapter 3.2.1 --- 17β-Estradiol on Cell Growth --- p.45
Chapter 3.2.2 --- 17β-Estradiol on Anticancer Drug Sensitivity --- p.45
Chapter 3.2.3 --- 17β-Estradiol and Doxorubicin on Cell Cycle Progression --- p.51
Chapter 3.2.4 --- 17β-Estradiol and Doxorubicin Induced DNA Fragmentation --- p.57
Chapter 3.2.5 --- 17β-Estradiol and Doxorubicin on Annexin Staining --- p.59
Chapter 3.2.6 --- 17β-Estradiol and Doxorubicin on Apoptotic Protein Expression --- p.62
Chapter 3.3 --- The Effect of Tamoxifen on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.64
Chapter 3.3.1 --- Tamoxifen on Cell Growth of Human --- p.65
Chapter 3.3.2 --- Tamoxifen on Anticancer Drug Sensitivity --- p.65
Chapter 3.3.3 --- Tamoxifen and Doxorubicin on Cell Cycle Progression --- p.71
Chapter 3.3.4 --- Tamoxifen and Doxorubicin Induced DNA Fragmentation --- p.76
Chapter 3.3.5 --- Tamoxifen and Doxorubicin on Annexin Staining --- p.78
Chapter 3.3.6 --- Tamoxifen and Doxorubicin on Apoptotic Protein Expression --- p.79
Chapter 3.4 --- The Effect of Aromatase Inhibtiors on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.81
Chapter 3.4.1 --- Aromatase Inhibitors on Cell Growth --- p.81
Chapter 3.4.2 --- Aromatase Inhibitors on Anticancer Drug Sensitivity --- p.83
Chapter 3.4.3 --- 4-AcA and Doxorubicin on Cell Cycle Progression --- p.93
Chapter 3.4.4 --- 4-AcA and Doxorubicin Induced DNA Fragmentation --- p.99
Chapter 3.4.5 --- 4-AcA and Doxorubicin on Annexin Staining --- p.100
Chapter 3.4.6 --- 4-AcA and Doxorubicin on Apoptotic Protein Expression --- p.102
Chapter 4. --- Discussion --- p.105
Chapter 4.1 --- 17 β-Estradiol and Anticancer Drug Sensitivity --- p.106
Chapter 4.2 --- Tamoxifen and Anticancer Drug Sensitivity --- p.109
Chapter 4.3 --- Aromatase Inhibitors and Anticancer Drug Sensitivity --- p.112
Chapter 4.4 --- DU145 Cells vs PC3 Cells --- p.115
Chapter 5. --- Conclusion and Perspectives --- p.116
Chapter 6. --- References --- p.117
Liu, Li Yang. "Association of Tissue Promoter Methylation Levels of APC, RASSF1A, CYP26A1, and TBX15 with Prostate Cancer Progression." Thesis, 2012. http://hdl.handle.net/1807/33724.
Повний текст джерелаLin, Feng-YI, and 林峰益. "The mechanisms of thapsigargininhibit telomerase activity and induce cell death via epigenetic modification in lung cancer cells." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/71285797003911440815.
Повний текст джерела中山醫學大學
醫學研究所
102
Thapsigargin (TG) was isolated from the Mediterranean plant Thapsia garganica. The highly lipophilic characteristic of TG accounts for their excellent penetration of biological membranes. TG can induce ER Stress and increase intracellular calcium through inhibiting sarco-endoplasmic reticulum Ca2+-ATPases. It has been reported that TG induces apoptosis and autophagy. In our previous study, TG inhibits telomerase activity by decreasing hTERT expression in A549 cells. In this study, we investigated the effects of TG on cytotoxicity, cell senescence and epigenetic regulation of hTERT. In our previous studies, fungal immunomodulatory protein Ganoderma tsugae (FIP-gts) has anticancer effects. FIP-gts can inhibit telomerase activity via ER Stress/calcium pahway in wide-type EGFR A549 cells. In this study, we investigated the effects of FIP-gts on telomerase activity and hTERT expression in EGFR mutation lung cancer cells. On MTT assay, the cell viability was reduced by TG in A549, H1355 and H1299 cells and reduced by FIP-gts in A549, H1975 and HCC827 cells. However, FIP-gts did not inhibit cell survival in H1650 cells. On clonogenic assay, TG inhibited A549 cell colony formation. Several autophagy inhibitors, 3-methyladenine (3-MA), chloroquine (CQ), and bafilomycin A1 (BafA1) were used to clarify the role of autophagy in TG-induced cell death. However, only 3-MA, an autophagy initiation inhibitor, enhanced the TG-induced cell-killing effect. The flow cytometry analysis was performed to detect the TG-induced ROS and senescence. Different from most of the genes, promoter hypermethylation turns on the hTERT expression. The TRAP, RT-PCR and Real Time PCR were used to analyze telomerase activity and hTERT expression in lung cancer cells treated with TG or FIP-gts. The western blot assay was performed to detected hTERT, TRF1 and TRF2 expression in A549 cells treated TG with or without 5-Azadc. The results demonstrated that 5-Azadc did not affect the TG-inhibiting telomerase activity and hTERT expression. DNA methyltransferase(DNMTs) enzyme are plays an important role that methylated genomic DNA. On RT-PCR and western blot assay, TG and 5-Azadc co-treatment downregulated the expressions of DNMT1 and DNMT3b, but did not alter the DNMT3a in A549 cells. To study the methylation patterns in more detail, bisulfite sequencing analysis confirm the hTERT promoter region (-196 form +46) in TG-treated cells. TG did not induce the methylation of site-specific CpGs on the hTERT promoter. The reporter assay was used to investigate of effect of transcription factors on hTERT promoter activity regulation. Thapsigargin inhibited the transcriptional activities of hTERT promoter (-548, -212, -196 and -155). Our results suggested that TG induces cell death via inhibited hTERT and telomerase activity. FIP-gts can inhibit cell survival and telomerase activity in EGFR mutation lung cancer cells.
Silva, Tânia Soraia Vieira da. "The role of macroH2A1 in prostate carcinogenesis." Master's thesis, 2015. http://hdl.handle.net/1822/41235.
Повний текст джерелаProstate cancer (PCa) is the most common noncutaneous malignancy in men and the major cause of cancer-related morbidity and mortality worldwide. Due to genetic and epigenetic deregulations, prostate cancer is characteristically asymptomatic in early stages. Deeper understanding of this mechanisms strength the development of new and improved diagnostic and prognostic tools and, therefore, better treatment strategies. The shuffle of canonical histones, an epigenetic mechanism, is highly conserved among species and expression alterations of these histones variants, such as macroH2A1, are related to cancer development. H2AFY gene codifies two isoforms of the H2A histone variant macroH2A1: macroH2A1.1 and macroH2A1.2. MacroH2A1.1 inhibits cell proliferation and cell migration, whilst macroH2A1.2 has opposite functions. To date, there were studies of this histone variant in several cancer types, but none in PCa. Thus, our aim was to assess whether macroH2A1 is implicated in prostate carcinogenesis. In a large series of prostate samples from Portuguese Oncology Institute-Porto, we found that macroH2A1.1 transcript levels were downregulated in high-grade prostatic intraepithelial neoplasia (PIN) and primary PCa compared to normal prostatic tissues. Moreover, QKI, a splicing regulator that induces macroH2A1.1 expression, presented similar results. Compared with clinicopathological data, macroH2A1.1 and QKI expression were associated with Gleason Score and PSA blood levels. Both transcripts were able to discriminate cancerous from noncancerous prostate tissues. MacroH2A1.1 in vitro overexpression in a PCa Cell line decreased cell viability. Thus, macroH2A1.1 seems to play a critical role in PCa development.
O cancro da próstata é, mundialmente, a neoplasia não-cutânea mais comum do sexo masculino e a maior causa de morbilidade e mortalidade associada ao cancro. Com alterações genéticas e epigenéticas, o cancro da próstata é, inicialmente, assintomático. Uma melhor compreensão sobre estes mecanismos oferece o desenvolvimento de novas e aperfeiçoadas análises diagnósticas e, posteriormente, uma melhor aplicação de tratamentos. A substituição das histonas canónicas, um mecanismo epigenético, encontra-se conservada ao longo da evolução. Alterações da expressão dessas variantes de histonas, como a macroH2A1, correlacionam-se com o desenvolvimento de cancro. O gene H2AFY codifica duas isoformas da variante macroH2A1, da família H2A: macroH2A1.1 e macroH2A1.2. Enquanto a macroH2A1.1 inibe a proliferação e a migração celular, a macroH2A1.2 tem consequências opostas. Até hoje, há registos desta variante de histona em diversos estudos de cancro, embora nenhum em cancro da próstata. Com base no que foi descrito, esta tese tem como principal objectivo determinar se a variante macroH2A1 está associada com o desenvolvimento do carcinoma da próstata. Utilizando uma longa série de amostras de próstata do Instituto Português de Oncologia – Porto, descobrimos que os níveis de transcrito da macroH2A1.1 se encontravam mais baixos em neoplasias intraepiteliais prostáticas (PIN) de alto grau e tecidos primários de cancro da próstata, quando comparados com tecidos nãoneoplásicos de próstata. Adicionalmente, o QKI, um regulador de splicing que induz a expressão da macroH2A1.1, demonstrou resultados semelhantes. Comparando com os dados clinico patológicos, a expressão dos genes macroH2A1.1 e QKI estão associados com o Gleason Score e níveis de PSA no sangue. Ambos os transcritos também discriminam significativamente tecidos primários de cancro da próstata de tecidos não neoplásicos. A sobreexpressão de macroH2A1.1 numa linha de cancro da próstata diminuiu a viabilidade celular. Assim, a macroH2A1.1 parece desempenhar um papel relevante no desenvolvimento de cancro da próstata.
Dias, Diana Soraia Ferreira. "Internship Report and Monography entitled“Epigenetic therapy applied to cancer – new challenges in biomedicine”." Master's thesis, 2021. http://hdl.handle.net/10316/98999.
Повний текст джерелаEpigenetics comprises the study modifications in gene expression patterns that do not alter the primary DNA sequence, involving the reversible chemical modification of DNA, RNA and histones. Epigenetic changes are regulated by sets of enzymes that add or remove specific epigenetic markers and alter the expression of associated genes, producing an epigenetic code. Chromatin has several independent epigenetic mechanisms involved in modifying its structure, among which DNA methylation, post-translational modification of histones and non-coding RNAs. DNA methylation is an important regulator of gene expression and comprises the transfer of a methyl group to the fifth position carbon of the cytosine carbon ring, giving rise to 5-methylcytosine (5mC), through the DNMTs family of enzymes. One of the most relevant and most studied post-translational modifications is histone acetylation, which influences chromatin structure. The acetylation of histones consists of the addition of acetyl groups from Acetyl-Coenzyme A (acetyl-coA), to histone core and tails catalyzed by the histone acetyltransferase (HAT) family of enzymes. Epigenetics is influenced by externa factors, such as diet and metabolism, and, contrary to genetic abnormalities, epigenetic changes have a reversible character and can thus recover the function of the affected genes. A new trend in te molecular mechansims of disease is the identification of epigenetic patterns with specific diseases, such as the hypermethylation of DNA in cancer. Thus, understanding the impact that epigenetic mechanisms have on human diseases is crucial to succeeding in reversing or stabilizing the worsening of these diseases, namely cancer. Based on this knowledge, the great potential of epigenetic therapies and the development of drugs capable of modulating the epigenetic profile emerges. Among the drugs that act on the epigenetic machinery, the histone deacetylases inhibitors (HDACi), histone methyltransferases inhibitors (HMTi), acetyltransferases (HATi), demethylases (HDMi) and, finally, DNA methyltransferases inhibitors (DNMTi). Furthermore, resistance to chemotherapy is a limiting factor in anti-tumor therapies and, therefore, the combination of epigenetic drugs with classical anti-tumor therapies increases the probability of treatment success. Epigenetics is based on a promising therapeutic approach and with numerous application opportunities in different areas of clinical practice. In this work a general introduction to epigenetics and epigenetic mechanisms is followed by a more deeper revision concerning the use of epigenetic drugs in the case of cancer.
A epigenética compreende o estudo das modificações do DNA, RNA e de histonas com impacto na expressão genética que não alteram a sequência primária do DNA. As mudanças epigenéticas consistem, regra geral, na adição e remoção de grupos químicos (marcadores epigenéticos) de um modo regulado por famílias de enzimas que ao adicionar e remover os marcadores epigenéticos específicos alteram a expressão dos genes associados, produzindo um código epigenético. A cromatina apresenta vários mecanismos epigenéticos independentes envolvidos na modificação da sua estrutura, dos quais se destaca, por serem os mais bem estudados, a metilação do DNA, as modificações pós-translacionais de histonas e RNAs não codificantes. De facto, a metilação do DNA é um importante regulador da expressão genética e compreende a transferência de um grupo metilo para o carbono da quinta posição do anel de carbono de citosina, originando a 5-metilcitosina (5mC), por intermédio da família de enzimas, metiltransferases, DNMTs. Uma das modificações pós-translacionais mais relevante e mais estudada é a acetilação de histonas, que tem influência na estrutura da cromatina. A acetilação de histonas consiste na adição de grupos acetilo da Acetil-Coenzima A (acetil-coA) às caudas e “core” das histonas pela família de enzimas acetiltransferases das histonas (HAT). As modificações epigenéticas têm a particularidade de ser afetadas pelo ambiente, metabolismo e pela dieta e, contrariamente às anormalidades genéticas, as modificações epigenéticas têm um caráter reversível, benéfico ou não, podendo desta forma recuperar-se a função/expressão dos genes afetados. Um dos desenvolvimentos mais recentes no âmbito da saúde , diz respeito à caracterização de padrões de modificações epigenéticas associadas a doenças específicas, como por exemplo a hipermetilação do DNA no caso do cancro. Assim, a compreensão do impacto que os mecanismos epigenéticos têm nas doenças humanas, é crucial para conseguir reverter ou estabilizar o agravamento destas doenças, nomeadamente do cancro. Com base neste conhecimento baseia-se o grande potencial das terapias epigenéticas e o desenvolvimento de fármacos capazes de modular o perfil epigenético. Dentro dos fármacos que atuam na maquinaria epigenética citam-se os inibidores das histonas desacetilases (iHDAC), inibidores das histonas metiltransferases (iHMTs), das acetiltransferases (iHATs), das desmetilases (iHDMs) e, por fim, os inibidores das DNA metiltransferases (iDNMTs).Ademais, a resistência à quimioterapia é um fator limitante nas terapias antitumorais e desta forma, a combinação de fármacos epigenéticos com as terapias clássicas anti-tumorais, aumentam a probabilidade de êxito do tratamento. A epigenética assenta numa abordagem terapêutica promissora e com inúmeras oportunidades de aplicações em diversas áreas da prática clínica. Neste trabalho farei, inicialmente, uma abordagem genérica da epigenética para, depois, e dada a novidade e impacto na saúde humana, concentrar a atenção em mecanismos relacionados com fármacos epigenéticos.
(8612079), Arpita S. Pal. "Identification of novel epigenetic mediators of erlotinib resistance in non-small cell lung cancer." Thesis, 2020.
Знайти повний текст джерелаLung cancer is the third most prevalent cancer in the world; however it is the leading cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of the lung cancer cases. The current strategies to treat NSCLC patients with frequent causal genetic mutations is through targeted therapeutics. Approximately 10-35% of NSCLC patient tumors have activated mutations in the Epidermal Growth Factor Receptor (EGFR) resulting in uncontrolled cellular proliferation. The standard-of care for such patients is EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs), a class of targeted therapeutics that specifically inhibit EGFR activity. One such EGFR-TKI used in this study is erlotinib. Following erlotinib treatment, tumors rapidly regress at first; however, over 50% of patients develop erlotinib resistance within a year post treatment. Development of resistance remains to be the major challenge in treatment of NSCLC using EGFR-TKIs such as erlotinib.
In approximately 60% of cases, acquired erlotinib resistance in patients is attributed to a secondary mutation in EGFR, whereas in about 20% of cases, activation of alternative signaling pathways is the reported mechanism. For the remaining 15-20% of cases the mechanism of resistance remains unknown. Therefore, it can be speculated that the common methods used to identify genetic mutations in tumors post erlotinib treatment, such as histologic analysis and genetic screening may fail to identify alterations in epigenetic mediators of erlotinib resistance, also including microRNAs (miRNAs). MiRNAs are short non-coding RNAs that post-transcriptionally negatively regulate their target transcripts. Hence, in this study two comprehensive screens were simultaneously conducted in erlotinib sensitive cells: 1) a genome-wide knock-out screen, conducted with the hypothesis that loss of function of certain genes drive erlotinib resistance, 2) a miRNA overexpression screen, conducted with the hypothesis that certain miRNAs drive the development of erlotinib resistance when overexpressed. The overreaching goal of the study was to identify novel drivers of erlotinib resistance such as microRNAs or other epigenetic factors in NSCLC.
The findings of this study led to the identification of a tumor suppressive protein and an epigenetic regulator, SUV420H2 (KMT5C) that has never been reported to be involved in erlotinib resistance. On the other hand, the miRNA overexpression screen identified five miRNAs that contribute to erlotinib resistance that were extensively analyzed using multiple bioinformatic tools. It was predicted that the miRNAs mediate erlotinib resistance via multiple pathways, owing to the ability of each miRNA to target multiple transcripts via partial complementarity. Importantly, a correlation between the two screens was identified clearly supporting the use of two simultaneous screens as a reliable technique to determine highly significant miRNA-target interactions. Overall, the findings from this study suggest that epigenetic factors, such as histone modifiers and miRNAs function as critical mediators of erlotinib resistance, possibly belonging to the 15-20% of NSCLC cases with unidentified mechanisms involved in erlotinib resistance.
Winger, Joseph G. "Diet and exercise intervention adherence and health-related outcomes among older long-term breast, prostate, and colorectal cancer survivors." Thesis, 2013. http://hdl.handle.net/1805/5068.
Повний текст джерелаGiven the numerous benefits of a healthy diet and exercise for cancer survivors, there has been an increase in the number of lifestyle intervention trials for this population in recent years. However, the extent to which adherence to a diet and exercise intervention predicts health-related outcomes among cancer survivors is currently unknown. To address this question, data from the Reach out to ENhancE Wellness in Older Cancer Survivors (RENEW) diet and exercise intervention trial were analyzed. RENEW was a yearlong telephone and mailed print intervention for 641 older (>65 years of age), overweight (body mass index: 25.0-39.9), long-term (>5 years post-diagnosis) survivors of colorectal, breast, and prostate cancer. Participants were randomized to the diet and exercise intervention or a delayed-intervention control condition. The RENEW telephone counseling sessions were based on determinants of behavior derived from Social Cognitive Theory (SCT) (e.g., building social support, enhancing self-efficacy). These factors have been hypothesized to improve health behaviors, which in turn should improve health outcomes. Thus, drawing on SCT and prior diet and exercise research with cancer survivors, I hypothesized that telephone counseling session attendance would be indirectly related to health-related outcomes (i.e., physical function, basic and advanced lower extremity function, mental health, and body mass index) through intervention-period strength and endurance exercise and dietary behavior (i.e., fruit and vegetable intake, saturated fat intake). The proposed model showed good fit to the data; however, not all of the hypothesized relationships were supported. Specifically, increased telephone counseling session attendance was related to engagement in all of the health behaviors over the intervention period. In turn, (a) increased endurance exercise was related to improvement in all of the health-related outcomes with the exception of mental health; (b) increased strength exercise was solely related to improved mental health; (c) increased fruit and vegetable intake was only related to improved basic lower extremity function; and (d) saturated fat intake was not related to any of the health-related outcomes. Taken together, these findings suggest that SCT determinants of behavior and the importance of session attendance should continue to be emphasized in diet and exercise interventions. Continued exploration of the relationship between adherence to a diet and exercise intervention and health-related outcomes will inform the development of more cost-effective and efficacious interventions for cancer and other medical populations.