Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silencing of tumor suppressor genes (TSGs), by DNA methylation, is well known in adult cancers. However, based on the "stem cell" theory of tumorigenesis, the early epigenetic events arising in malignant precursors remain unknown. A recent report demonstrates that, while pluripotent embryonic stem cells lack DNA methylation and possess a "bivalent" pattern of activating and repressive histone marks in numerous TSGs, analogous multipotent malignant cells derived from germ cell tumors (embryonic carcinoma cells) gain additional silencing modifications to those same genes. These results suggest a possible mechanism by which aberrant differentiation, mediated by histone and DNA methylation, instigates tumor progression.
 ...
PMID:Epigenetic "bivalently marked" process of cancer stem cell-driven tumorigenesis. 1768 87

To understand the mechanisms of PTEN inactivation, which is reported to be involved in tumor progression and drug resistance in lung cancer, we analyzed the expression levels of PTEN at mRNA and protein levels, along with the genetic and epigenetic status of the PTEN gene, in a panel of lung cancer cell lines. Western blot analysis showed that six out of 25 (24%) cell lines displayed low expression of PTEN protein. The level of PTEN mRNA correlated well with corresponding protein expression in each of these six cell lines. In two of the six cell lines genomic analysis revealed homozygous deletions of the PTEN gene. Another two of the six cell lines displayed hypermethylation of the PTEN gene promoter assessed by methylation-specific PCR. The levels of PTEN mRNA and protein expression in PC9/f9 and PC9/f14 cells, which are gefitinib-resistant derivatives of the gefitinib-sensitive cell line, PC9, were reduced compared to the parental line. After treatment with the demethylating agent 5-aza-2'deoxycytidine (5-AZA) and the histone deacetyltransferase (HDAC) inhibitor Trichostatin A (TSA), the expression levels of PTEN mRNA and protein in these four cell lines (PC9/f9, PC9/f14, PC10 and PC14) were actually restored. In summary, reduction in PTEN protein expression was regulated by histone deacetylation and hypermethylation of the gene promoter, as well as homozygous deletion. In addition, we demonstrated that the combination treatment of gefitinib and TSA induced significant growth inhibition in gefitinib-resistant PC9/f9 and PC9/f14 cells. These findings suggest that the combination of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib with the demethylating agent 5-AZA and the HDAC inhibitor TSA may be a useful strategy for the treatment of some lung cancers.
 ...
PMID:PTEN inactivation in lung cancer cells and the effect of its recovery on treatment with epidermal growth factor receptor tyrosine kinase inhibitors. 1791 43

Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the development of blood vessels. Using small interfering RNAs, we observed that HDAC7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis. Among several factors known to be involved in angiogenesis, platelet-derived growth factor-B (PDGF-B) and its receptor (PDGFR-beta) were the most upregulated genes following HDAC7 silencing. We demonstrated that their increased expression induced by HDAC7 silencing was partially responsible for the inhibition of endothelial cell migration. In addition, we have also shown that treatment of endothelial cells with phorbol 12-myristate 13-acetate resulted in the exportation of HDAC7 out of the nucleus through a protein kinase C/protein kinase D activation pathway and induced, similarly to HDAC7 silencing, an increase in PDGF-B expression, as well as a partial inhibition of endothelial cell migration. Collectively, these data identified HDAC7 as a key modulator of endothelial cell migration and hence angiogenesis, at least in part, by regulating PDGF-B/PDGFR-beta gene expression. Because angiogenesis is required for tumor progression, HDAC7 may represent a rational target for therapeutic intervention against cancer.
 ...
PMID:Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. 1794 1

Endocrine signaling via nuclear receptors (NRs) is known to play an important role in normal physiology as well as in human tumor progression. Hormones regulate gene expression by altering local chromatin structure and, thereby, accessibility of transcriptional co-regulators to DNA. Recently it has been shown that non-histone proteins involved in hormone signaling, such as nuclear receptors and NR co-activators, are regulated by acetylation, resulting in their altered transcriptional activity. NAD-dependent protein deacetylases, the sirtuins (Sir2-related enzymes), directly modify NRs. Because sirtuins have been shown to regulate tumor cellular growth, aging, metabolic signaling and endocrine hormone signaling, they might play a role in cancer progression. This review focuses on the role of acetylation and the sirtuins in nuclear hormone receptor signaling.
 ...
PMID:Sirtuins, nuclear hormone receptor acetylation and transcriptional regulation. 1796 99

The Polycomb Group (PcG) protein EZH2 is a critical component of a multiprotein complex that methylates Lys(27) of histone 3 (H3K27), which consequently leads to the repression of target gene expression. We have previously reported that EZH2 is overexpressed in metastatic prostate cancer and is a marker of aggressive diseases in clinically localized solid tumors. However, the global set of genes directly regulated by PcG in tumors is largely unknown, and thus how PcG mediates tumor progression remains unclear. Herein we mapped genome-wide H3K27 methylation in aggressive, disseminated human prostate cancer tissues. Integrative analysis revealed that a significant subset of these genes are also targets of PcG in embryonic stem cells, and their repression in tumors is associated with poor prognosis. By stepwise cross-validation, we developed a "Polycomb repression signature" composed of 14 direct targets of PcG in metastatic tumors. Notably, solid tumor subtypes in which this gene signature is repressed show poor clinical outcome in multiple microarray data sets of tumors including breast and prostate cancer. Taken together, our results show a fingerprint of PcG-mediated transcriptional repression in metastatic prostate cancer that is reminiscent of stem cells and associated with cancer progression. Therefore, PcG proteins play a central role in the epigenetic silencing of target genes and functionally link stem cells, metastasis, and cancer survival.
 ...
PMID:A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. 1800 6

Polycomb-group genes (PcG), identified by Drosophila genetics, are believed to maintain positional information by constituting a cellular memory system. Recently this system has been proved to be supported by epigenetic transcription regulation. PcG products comprise two distinct complexes, PcG complex 1 and 2. First PcG complex 2 silences chromatin and encodes a histone code by methylating histone H3 at lysine 27. PcG complex 1 is, then, recruited by recognizing the histone code, and ubiquitinates histone H2A and/or inhibits chromatin remodeling to maintain the silenced states of the locus. Biologically, PcG-deficient mice provided biological evidence that PcG are essential for sustaining stem cell activity. More recently PcG were reported to be correlated with cancer progression and prognosis as well as with cancer stem cell activity. PcG may thus play a crucial part in sustaining the activities of malignant as well as normal stem cells. Although PcG were initially seen to maintain stem cell activity through repression of the INK4a locus, they now appear to perform more diverse functions in supporting stem cells. This paper summarizes current information on the molecular roles of PcG in normal and malignant stem cells and discusses the implications in future cancer therapy and regenerative medicine.
 ...
PMID:Role of Polycomb-group genes in sustaining activities of normal and malignant stem cells. 1822 10

A body of evidence accumulated over the past decade suggests that epigenetic mechanisms play an essential role in maintaining important cellular functions. Changes in epigenetic patterns (mainly DNA hyper- and hypomethylation and, more recently, histone modifications) may contribute to the development of cancer. Aberrant epigenetic events expand thorough tumor progression from the earliest to latest stages, therefore they can serve as convenient markers for detection and prognosis of cancer. The potential reversibility of epigenetic states in the tumor cell is an attractive target for cancer therapy. Much of our current knowledge on epigenetic alternations in cancer comes from studies on gastrointestinal malignancies, mainly on colorectal cancer, which currently serves as a model for epigenetic tumorigenesis. This review summarizes the current knowledge of epigenetic changes in gastrointestinal cancers and how this relates directly to disease progression and prognosis.
 ...
PMID:Aberrant epigenetic patterns in the etiology of gastrointestinal cancers. 1826 64

Over the past few years, the histone deacetylase (HDAC) inhibitors have occupied an important place in the effort to develop novel, but less toxic, anticancer therapy. HDAC inhibitors block HDACs, which are the enzymes responsible for histone deacetylation, and therefore they modulate gene expression. The cellular effects of HDAC inhibitors include growth arrest and the induction of differentiation. Early successes in cancer therapeutics obtained using these drugs alone or in combination with other anticancer drugs emphasize the important place of posttranslational modifications of histones in cancer therapy. Histone tail modifications along with DNA methylation are the most studied epigenetic events related to cancer progression. Moreover, extranuclear functions of histones have also been described. Because HDAC inhibitors block HDACs and thereby increase histone acetylation, we propose a model wherein exogenous acetylated histones or other related acetylated proteins that are introduced into the nucleus become HDAC substrates and thereby compete with endogenous histones for HDACs. This competition may lead to the increased acetylation of the endogenous histones, as in the case of HDAC inhibitor therapy. Moreover, other mechanisms of action, such as binding to chromatin and modulating gene expression, are also possible for exogenously introduced histones.
 ...
PMID:Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics. 1841 89

The human gene MUC4 encodes a transmembrane mucin, ligand of ErbB2, that is associated with pancreatic tumor progression. In the normal pancreas, MUC4 is not expressed, whereas activation of its expression is observed in the early steps of pancreatic carcinogenesis. The molecular mechanisms responsible for MUC4 gene activation are however still unknown. The MUC4 5'-flanking region being GC-rich and including two CpG islands, we hypothesized that epigenetic regulation may be involved and undertook to decipher the molecular phenomenons implied. By treating cancer cell lines with 5-aza-2'-deoxycytidine (5-aza) and trichostatin A (TSA), we were able to restore MUC4 expression in a cell-specific manner. We showed by bisulfite-treated genomic DNA sequencing and chromatin immunoprecipitation that methylation of five CpG sites and establishment of a repressive histone code at the 5'-untranslated region were associated with MUC4 silencing and impaired its activation by Sp1. Direct involvement of DNMT3A, DNMT3B, HDAC1, and HDAC3 was demonstrated by RNA interference and chromatin immunoprecipitation. Moreover, inhibition of histone deacetylation by TSA was associated with strong MUC4 repression in high-expressing cells. In conclusion, this work shows for the first time the importance of epigenetics in regulating MUC4 expression and may represent a new strategy to inhibit its expression in epithelial tumors.
 ...
PMID:Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and histone deacetylases. 1849 26

Cellular stress by DNA damage induces checkpoint kinase-2 (CHK2)-mediated phosphorylation and stabilization of the E2F1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic E2F1 target genes, including Apaf1 and p73. This report characterizes an interaction between the aryl hydrocarbon (Ah) receptor (AHR), a ligand-activated transcription factor, and E2F1 that results in the attenuation of E2F1-mediated apoptosis. In Ahr(-/-) fibroblasts stably transfected with a doxycycline-regulated AHR expression vector, inhibition of AHR expression causes a significant elevation of oxidative stress, gammaH2A.X histone phosphorylation, and E2F1-dependent apoptosis, which can be blocked by small interfering RNA-mediated knockdown of E2F1 expression. In contrast, ligand-dependent AHR activation protects these cells from etoposide-induced cell death. In cells expressing both proteins, AHR and E2F1 interact independently of the retinoblastoma protein (RB), because AHR and E2F1 coimmunoprecipitate from extracts of RB-negative cells. Additionally, chromatin immunoprecipitation assays indicate that AHR and E2F1 bind to the Apaf1 promoter at a region containing a consensus E2F1 binding site but no AHR binding sites. AHR activation represses Apaf1 and TAp73 mRNA induction by a constitutively active CHK2 expression vector. Furthermore, AHR overexpression blocks the transcriptional induction of Apaf1 and p73 and the accumulation of sub-G(0)/G(1) cells resulting from ectopic overexpression of E2F1. These results point to a proproliferative, antiapoptotic function of the Ah receptor that likely plays a role in tumor progression.
 ...
PMID:The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. 1852 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>