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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epigenetic gene regulation is a key determinant of heritable gene expression patterns and is critical for normal cellular function. Dysregulation of epigenetic transcriptional control is a fundamental feature of cancer, particularly manifesting as increased promoter DNA methylation with associated aberrant gene silencing, which plays a significant role in tumor progression. We now globally map key chromatin parameters for genes with promoter CpG island DNA hypermethylation in colon cancer cells by combining microarray gene expression analyses with chromatin immunoprecipitation-on-chip technology. We first show that the silent state of such genes universally correlates with a broad distribution of a low but distinct level of the PcG-mediated histone modification, methylation of lysine 27 of histone 3 (H3K27me), and a very low level of the active mark H3K4me2. This chromatin pattern, and particularly H3K4me2 levels, crisply separates DNA-hypermethylated genes from those where histone deacetylation is responsible for transcriptional silencing. Moreover, the chromatin pattern can markedly enhance identification of truly silent and DNA-hypermethylated genes. We additionally find that when DNA-hypermethylated genes are demethylated and reexpressed, they adopt a bivalent chromatin pattern, which is associated with the poised gene expression state of a large group of embryonic stem cell genes and is characterized by an increase in levels of both the H3K27me3 and H3K4me2 marks. Our data have great relevance for the increasing interest in reexpression of DNA-hypermethylated genes for the treatment of cancer.
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PMID:Defining a chromatin pattern that characterizes DNA-hypermethylated genes in colon cancer cells. 1863 28

Prometastatic gene expression events occur during the early phases of prostate oncogenesis, even though overlaping with genes that induce primary cancer growth. Cytogenetic and genomic profiling analyses have identified many cancer-associated chromosomal abnormalities consisting mainly in losses in the early phases of sporadic primary prostate carcinoma. Metastatic genes are those in which gains in oncogene functional activity or lack of tumor suppressor genes enable cancer cells to detach, escape into the circulation, penetrate and colonize distant organs. In metastatic prostate carcinoma some genes, such as MTA1 and MYBL2, are differentially upregulated in comparison to primary site, while IGFBP, DAN1, FAT and RAB5A appear to be downregulated. Epigenetic alterations, such as histone deacetylation/hypermethylation, are also involved in the metastasis promotion. Nevertheless, during oncogenesis and cancer progression, prostate cancer cells may regain pluripotent stem cell-like properties or, as an alternative, may be, them selves, malignant stem cell clones, equipped with self-renewal mechanisms. Pleiotropic contributions to cancer progression and metastatic spread are also brought up from a variety of tumor microenvironment-associated factors. Moreover, inflammatory processes can partecipate in prostate tumorigenesis and cancer progression through several mechanisms, such as generation of both oxygen and nitrogen reactive species, induction of cyclooxygenase-2 and production of growth factors and cytokines by neutrophils and macrophages of host microenvironment. The knowledge of both genetic and microenvironmental cancer aggressiveness factors is necessary to define timing and suitability of therapeutical strategies.
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PMID:Genetic and microenvironmental implications in prostate cancer progression and metastasis. 1870 Jun 88

EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that targets lysine-27 of histone H3. This methylated H3-K27 chromatin mark is commonly associated with silencing of differentiation genes in organisms ranging from plants to flies to humans. Studies on human tumors show that EZH2 is frequently over-expressed in a wide variety of cancerous tissue types, including prostate and breast. Although the mechanistic contributions of EZH2 to cancer progression are not yet determined, functional links between EZH2-mediated histone methylation and DNA methylation suggest partnership with the gene silencing machinery implicated in tumor suppressor loss. Here we review the basic molecular biology of EZH2 and the findings that implicate EZH2 in different cancers. We also discuss EZH2 connections to other silencing enzymes, such as DNA methyltransferases and histone deacetylases, and we consider progress on deciphering mechanistic consequences of EZH2 overabundance and its potential roles in tumorigenesis. Finally, we review recent findings that link EZH2 roles in stem cells and cancer, and we consider prospects for integrating EZH2 blockade into strategies for developing epigenetic therapies.
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PMID:Roles of the EZH2 histone methyltransferase in cancer epigenetics. 1872 33

Cancer in humans is the result of a multi-step process. This process often involves the activation of oncogenes and/or the inactivation of tumor suppressor genes. These two steps arise not only due to mutations, but can also be the result of a translocation or an altered transcription rate. One important mechanism is the occurrence of epigenetic alterations like promotor methylation (which may lead to tumor suppressor silencing) or decreased histone acetylation (which can result in the downregulation of proteins involved in apoptosis). Today, histone acetylation and DNA methylation are epigenetic modifications which have been linked closely to the pathology of human cancers and inhibitors of both enzyme classes for clinical use are at hand. In contrast, other fields of epigenetics still lack of similarly thorough knowledge. This is especially true for the group of histone methyltransferases and their inhibitors. Since connections between histone methylation patterns and cancer progression have been recognized, histone methyltransferases represent promising targets for future cancer treatment.
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PMID:Cancer treatment of the future: inhibitors of histone methyltransferases. 1877 66

It has been shown that epigenetic modifications play an important role in tumorigenesis. Thus, affecting epigenetic tumorigenic alterations can represent a promising strategy for anticancer targeted therapy. Among the key chromatin modifying enzymes which influence gene expression, histone acetyltransferases (HATs) and histone deacetylases (HDACs) have recently attracted interest because of their impact on tumor development and progression. Increased expression of HDACs and disrupted activities of HATs have been found in several tumor types, with a consequent hypoacetylated state of chromatin that can be strictly correlated with low expression of either tumor suppressor or pro-apoptotic genes. Histone deacetylase inhibitors (HDACIs) represent a new and promising class of antitumor drugs that influence gene expression by enhancing acetylation of histones in specific chromatin domains. HDACIs have been shown to exert potent anticancer activities inducing cell cycle arrest and apoptosis. Notably, a high efficacy of these drugs has been selectively revealed in malignant cells rather than in normal cells. Moreover, the therapeutic potential of these agents is also supported by the evidence that HDACIs downregulate genes involved in tumor progression, invasion and angiogenesis. Several HDACIs are currently under clinical investigation, including vorinostat (SAHA), romidepsin (depsipeptide, FK-228), LAQ824/LBH589 and belinostat (PXD101), compounds that have shown therapeutic potential in many types of malignancies including solid tumors. Based on the ability of HDACIs to regulate many signaling pathways, co-treatment of these compounds with molecular targeted drugs is a promising strategy against many types of tumors.
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PMID:Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review). 1881 76

A mismatch between metabolic demand and oxygen delivery leads to microenvironmental changes in solid tumors. The resulting tumor hypoxia is associated with malignant progression, therapy resistance and poor prognosis. However, the molecular mechanisms underlying therapy resistance in hypoxic tumors are not fully understood. The hypoxia-inducible factor (HIF) is a master transcriptional activator of oxygen-regulated gene expression. Transformed mouse embryonic fibroblasts (MEFs) derived from HIF-1alpha-deficient mice are a popular model to study HIF function in tumor progression. We previously found increased chemotherapy and irradiation susceptibility in the absence of HIF-1alpha. Here, we show by single-cell electrophoresis, histone 2AX phosphorylation and nuclear foci formation of gammaH2AX and 53BP1, that the number of DNA double-strand breaks (DSB) is increased in untreated and etoposide-treated HIF-deficient MEFs. In etoposide-treated cells, cell cycle control and p53-dependent gene expression were not affected by the absence of HIF-1alpha. Using a candidate gene approach to screen 17 genes involved in DNA repair, messenger RNA (mRNA) and protein of three members of the DNA-dependent protein kinase complex were found to be decreased in HIF-deficient MEFs. Of note, residual HIF-1alpha protein in cancer cells with a partial HIF-1alpha mRNA knockdown was sufficient to confer chemoresistance. In summary, these data establish a novel molecular link between HIF and DNA DSB repair. We suggest that selection of early, non-hypoxic tumor cells expressing low levels of HIF-1alpha might contribute to HIF-dependent tumor therapy resistance.
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PMID:Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1 alpha-deficient mouse embryonic fibroblasts. 1884 80

All cells of a given organism contain nearly identical genetic information, yet tissues display unique gene expression profiles. This specificity is in part due to transcriptional control by epigenetic mechanisms that involve post-translational modifications of histones. These modifications affect the folding of the chromatin fiber and serve as binding sites for non-histone chromosomal proteins. Here we discuss functions of the Heterochromatin Protein 1 (HP1) family of proteins that recognize H3K9me, an epigenetic mark generated by the histone methyltransferases SU(VAR)3-9 and orthologues. Loss of HP1 proteins causes chromosome segregation defects and lethality in some organisms; a reduction in levels of HP1 family members is associated with cancer progression in humans. These consequences are likely due to the role of HP1 in centromere stability, telomere capping and the regulation of euchromatic and heterochromatic gene expression.
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PMID:Linking Heterochromatin Protein 1 (HP1) to cancer progression. 1892 34

Malignant tumors of childhood represent a rather heterogeneous group of neoplasms originating from virtually any anatomical structure. Despite major improvements in the clinical management including timely diagnosis, advanced supportive care and refined multimodality treatment, prognosis remains grim for certain risk groups. Aberrant epigenetic regulation, i.e. changes in gene transcription not due to DNA sequence alterations, is now increasingly recognized as a fundamental process in malignant transformation, tumor progression and drug resistance. The molecular mechanisms involve aberrant activity of enzymes controlling the packaging and transcriptional regulation of the genome. Two major protein families are involved in this process, DNA methyltransferases and histone deacetylases. With the availability of small molecule inhibitors targeting the aberrant epigenetic machinery in cancer cells, these compounds are evaluated in several clinical trials.
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PMID:The epigenetics of cancer in children. 1894 67

The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild side-effects, this intervention has nowadays become the treatment of choice for patients with advanced breast and prostate cancer, provided that their tumors express hormone receptors. However, in case of breast cancer it is well known that part of the patients have hormone receptor-negative tumors at diagnosis, whereas other patients have discordant receptor expression across lesions. In addition, receptor expression can change during therapy and result in resistance to this therapy. Besides several lines of hormonal treatments, also other strategies to affect the hormone receptors are currently under investigation, namely histone deacetylases (HDAC) and heat shock protein (HSP) inhibitors. Knowledge of the actual receptor status can support optimal treatment decision-making and the evaluation of new drugs. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows monitoring and quantification of hormone receptor expression across lesions throughout the body. Several PET tracers have been developed for imaging of the most relevant hormone receptors in breast and prostate cancer: i.e. the estrogen, progesterone and androgen receptors. Some of these PET tracers have been successfully applied in early clinical studies. This review will give an overview of the current status of PET imaging of hormone receptors in breast and prostate cancer.
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PMID:PET imaging of steroid receptor expression in breast and prostate cancer. 1899 16

The interplay between histone modifications and promoter hypermethylation provides a causative explanation for epigenetic gene silencing in cancer. Less is known about the upstream initiators that direct this process. Here, we report that the Cystatin M (CST6) tumor suppressor gene is concurrently down-regulated with other loci in breast epithelial cells cocultured with cancer-associated fibroblasts (CAF). Promoter hypermethylation of CST6 is associated with aberrant AKT1 activation in epithelial cells, as well as the disabled INNP4B regulator resulting from the suppression by CAFs. Repressive chromatin, marked by trimethyl-H3K27 and dimethyl-H3K9, and de novo DNA methylation is established at the promoter. The findings suggest that microenvironmental stimuli are triggers in this epigenetic cascade, leading to the long-term silencing of CST6 in breast tumors. Our present findings implicate a causal mechanism defining how tumor stromal fibroblasts support neoplastic progression by manipulating the epigenome of mammary epithelial cells. The result also highlights the importance of direct cell-cell contact between epithelial cells and the surrounding fibroblasts that confer this epigenetic perturbation. Because this two-way interaction is anticipated, the described coculture system can be used to determine the effect of epithelial factors on fibroblasts in future studies.
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PMID:Breast cancer-associated fibroblasts confer AKT1-mediated epigenetic silencing of Cystatin M in epithelial cells. 1907 94


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