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At least 721 records · Page 40Linked to original sources
PubMed2006

Host epigenetic modifications by oncogenic viruses.

Epigenetic alterations represent an important step in the initiation and progression of most human cancers, but it is difficult to differentiate the early cancer causing alterations from later consequences. Oncogenic viruses can induce transformation via expression of only a small number of viral genes. Therefore, the mechanisms by which oncogenic viruses cause cancer may provide clues as to which epigenetic alterations are critical in early carcinogenesis.

Epigenesis, Genetic↗
PubMed2005

Epigenetic alterations in gastric carcinogenesis.

Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.

Adenocarcinoma↗
PubMed2006

Hsp90 at the crossroads of genetics and epigenetics.

Hsp90 is a specialized molecular chaperone that is capable of buffering the expression of abnormal phenotypes. Inhibition of Hsp90 activity results in the expression of these phenotypes that are otherwise masked. Selection of offspring from the crossing of affected progenies results in inheritance and enrichment of these phenotypes, which can become independent of their original stimuli. The current combined evidence favours a model involving the interplay between genetics and epigenetics. The recent proteomics efforts to characterize the Hsp90 interaction networks provide further clues into the molecular mechanisms behind this complex phenomenon. This review summarizes the most recent experimental observations and briefly discusses the genetic and epigenetic views used in explaining the different observations.

Animals↗
PubMed2004

Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes.

Post-translational modifications of histone amino termini are thought to convey epigenetic information that extends the coding potential of DNA. In particular, histone lysine methylation has been implicated in conveying transcriptional memory and maintaining lineage fidelity. Here an analysis of histone lysine methylation in quiescent (G(0)) and cycling lymphocytes showed that methylation of histone H3 at lysines 4 (H3K4), 9 (H3K9), 27 (H3K27) and histone H4 at lysine 20 is markedly reduced in resting B lymphocytes as compared with cycling cells. Quiescent B cells also lacked heterochromatin-associated HP1beta and Ikaros at pericentric chromatin and expressed low levels of Ezh2 and ESET histone methyl transferases (HMTases). Nuclei from resting B or T cells were approximately three times more efficiently reprogrammed in nuclear transfer assays than cells in which HMTase expression, histone methylation and HP1beta binding had been restored following mitotic stimulation. These results showing local and global changes in histone lysine methylation levels in vivo demonstrate that constitutive heterochromatin organization is modified in resting lymphocytes and suggest that histone hypomethylation is a useful indicator of epigenetic plasticity.

Animals↗
PubMed2006

A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory.

DNA demethylation plays a critical role in transcriptional regulation in differentiated somatic cells. However, there is no experimental evidence that CpG methylation in a small region of a genome restricts gene expression. Here, we show that the anti-CD3repsilon/CD28 antibody stimulation of human CD4+ T cells induces IL2 expression following epigenetic changes, including active demethylation of a specific CpG site, recruitment of Oct-1, and changes in histone modifications. When the stimulatory signal is withdrawn, Oct-1 remains on the enhancer region as a stable marker of the stimulation, causing the second induction to be faster and stronger. Our observations indicate that Oct-1-binding followed by CpG demethylation are key events in the epigenetic regulation of IL2 expression and may act as a memory of the regulatory event.

Breast Neoplasms↗
PubMed2006

Epigenetic inactivation of tumor suppressor genes in serum of patients with cutaneous melanoma.

Small amounts of cell-free DNA circulate in both healthy and diseased human blood, while increased concentrations of DNA are present in the serum of cancer patients. Tumor-specific mutations or epigenetic modifications have predominantly been detected in tissue specimens. The purpose of this study was to investigate methylation of five different genes involved in tumor suppression and DNA repair (suppressors of cytokine signaling 1 and 2 (SOCS1, SOCS2)), Ras-association domain family protein 1A (RASSF1a), D-type p16(INK4a) cyclin-dependent kinase inhibitor (CDKN), and O6-methylguanine DNA-methyltransferase (MGMT)) in the serum of 100 patients using methylation-specific PCR. In all, 41 melanoma patients (stage I = 18; stage II = 10; stage III/IV = 13), 13 healthy controls without nevi, and 10 individuals with more than 15 nevi of >5 mm in size were investigated. For comparison, sera from patients with other skin tumors (nine basal cell cancers, five Kaposi's sarcoma), different metastasized cancers (five breast cancers, five colon cancers), and several chronic inflammatory diseases (n = 12) were also analyzed. In addition, we examined if methylation was involved in silencing transcription of these genes in 12 melanoma specimens. SOCS1, SOCS2, RASSF1a, CDKN2a, and MGMT were methylated in 75, 43, 64, 75, and 64% of melanoma samples, respectively. Of the 41 melanoma patients, 83% had one hypermethylated gene, while 66, 51, and 41% had two, three, or four hypermethylated genes, respectively. Also, 20% of these patients showed hypermethylation for all genes, while only 17% showed no methylation. Importantly, the methylation profile of the selected genes from melanoma patients was distinct from the other analyzed tumors. Transcription of SOCS1, SOCS2, CDKN2a, and RASSF1a genes was significantly reduced in fresh melanoma samples, while MGMT showed a 12-fold upregulation at the messenger ribonucleic acid level (P < 0.001). Our findings suggest that epigenetic silencing of the studied tumor suppressor genes is a common and probably important mechanism for melanoma formation. This convenient method using a simple blood sample may contribute to classification of melanoma and awaits clinical validation.

Adult↗
PubMed2000

Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome.

Germ-line mutations of the LKB1 gene cause Peutz-Jeghers syndrome (PJS) characterized by mucocutaneous pigmentation, predisposition to benign hamartomas of the gastrointestinal tract and also to several types of tumors. However, somatic mutations of this gene are very rare. To examine inactivation of LKB1 by epigenetic mechanisms, we investigated a series of primary tumors and cancer cell lines, for hypermethylation affecting the CpG island located in the 5' region of the LKB1 gene using Methylation-specific PCR (MSP). First, we screened 51 cancer cell lines. Only three colorectal and one cervical carcinoma cell lines were methylated at LKB1, and loss of the LKB1 transcript was demonstrated. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored LKB1 expression. To address the incidence of LKB1 epigenetic inactivation in primary tumors, we analysed colorectal, breast, gastric, pancreatic, thyroid, bladder and testicular carcinomas (n=195). Normal tissues from the mentioned organs were unmethylated in this region. Among the described tumors, only one colorectal carcinoma and three testicular tumors displayed LKB1 promoter hypermethylation. Further study of those histological types more commonly associated with PJS, demonstrated that LKB1 promoter hypermethylation was present in five of 11 (45%) papillary breast carcinomas. Finally, in three patients with a strong family story suggestive of PJS disease, abnormal LKB1 methylation was found in four of 22 (18%) hamartomatous polyps lesions. Our findings provide an alternative pathway for inactivation of the LKB1 tumor suppressor gene involving promoter hypermethylation.

AMP-Activated Protein Kinase Kinases↗
PubMed2002

Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors.

The genetic nature of testicular germ cell tumors and the molecular mechanisms underlying the morphological and clinical differences between the two subtypes, seminomas and nonseminomas, remains unclear. Genetic studies show that both subtypes exhibit many of the same regional genomic disruptions, although the frequencies vary and few clear differences are found. We demonstrate significant epigenetic differences between seminomas and nonseminomas by restriction landmark genomic scanning. Seminomas show almost no CpG island methylation, in contrast to nonseminomas that show CpG island methylation at a level similar to other solid tumors. We find an average of 1.11% of CpG islands methylation in nonseminomas, but only 0.08% methylated in seminomas. Furthermore, we demonstrate that seminomas are more highly hypomethylated than nonseminomas throughout their genome. Since both subtypes are thought to arise from primordial germ cells, the epigenetic differences seen between these subtypes may reflect the normal developmental switch in primordial germ cells from an undermethylated genome to a normally methylated genome. We discuss these findings in relation to different developmental models for seminomatous and nonseminomatous testicular germ cell tumors.

Blotting, Southern↗
PubMed2003

Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers.

Many distinct regions of 3p show frequent allelic losses in a wide range of tumour types. Previously, the BLU candidate tumour suppressor gene (TSG) encoded by a gene-rich critical deleted region in 3p21.3 was found to be inactivated rarely in lung cancer, although expression was downregulated in a subset of lung tumour cell lines. To elucidate the role of BLU in tumorigenesis, we analysed BLU promoter methylation status in tumour cell lines and detected promoter region hypermethylation in 39% lung, 42% breast, 50% kidney, 86% neuroblastoma and 80% nasopharyngeal (NPC) tumour cell lines. Methylation of the BLU promoter region correlated with the downregulation of BLU transcript expression in tumour cell lines. Expression was recovered in tumour cell lines treated with 5-aza 2-deoxycytidine. Exogenous expression of BLU in neuroblastoma (SK-N-SH) and NSCLC (NCI-H1299) resulted in reduced colony formation efficiency, in vitro. Furthermore, methylation of the BLU promoter region was detected in primary sporadic SCLC (14%), NSCLC (19%) and neuroblastoma (41%). As frequent methylation of the RASSF1A 3p21.3 TSG has also been reported in these tumour types, we investigated whether BLU and RASSF1A methylation were independent or related events. No correlation was found between hypermethylation of RASSF1A and BLU promoter region CpG islands in SCLC or neuroblastoma. However, there was association between RASSF1A and BLU methylation in NSCLC (P=0.0031). Our data suggest that in SCLC and neuroblastoma, RASSF1A and BLU methylations are unrelated events and not a manifestation of a regional alteration in epigenetic status, while in NSCLC there may be a regional methylation effect. Together, these data suggest a significant role for epigenetic inactivation of BLU in the pathogenesis of common human cancers and that methylation inactivation of BLU occurs independent of RASSF1A in SCLC and neuroblastoma tumours.

Base Sequence↗
PubMed2003

Epigenetic targets in hematopoietic malignancies.

Frequent genetic alterations in hematopoietic neoplasias (chromosomal translocations, point mutations, etc.) have provided biologic targets for the development of effective novel therapies. A rapidly increasing body of knowledge provides evidence also for multiple epigenetic alterations in these disorders, which can complement or even precede genetic aberrations. Gene inactivation ('silencing') of tumor suppressor and growth inhibitory genes (e.g. the cyclin-dependent kinase inhibitors p16, p15, p21) is frequently mediated by DNA methylation of gene promoters. The acetylation state of histones (functionally linked to the DNA methylation state by the methylcytosine binding protein 2, recruiting histone deacetylases) provides a second major epigenetic silencing mechanism. Therapeutic reversal strategies are being developed for acute leukemias, myelodysplastic syndromes and malignant lymphomas. Since the discovery of the DNA methyltransferase (Dnmt) inhibitory activity of two azanucleosides (5-azacytidine, 5-aza-2'-deoxycytidine/decitabine) even at doses with minimal nonhematologic toxicity, both have been clinically studied in several myeloid neoplasias, particularly in elderly patients unable to tolerate aggressive treatment. Further development of agents counteracting aberrant methylation is directed at more targeted approaches, for example, antisense molecules against Dnmts. Histone deacetylases (HDACs) can be inhibited by numerous compounds (sodium phenylbutyrate, valproic acid, novel compounds such as depsipeptide), which have entered the clinical arena in similar indications as Dnmt inhibitors. Impressive effects of HDAC inhibition in acute promyelocytic leukemia models (PML/RARA expression) translate the finding of HDAC recruitment by this chimeric transcription factor to its target genes. The recent discovery of recruitment by PML/RARA also of Dnmt activity to the retinoic acid receptor-beta promoter makes it an interesting candidate for Dnmt inhibitors. Studies combining a 're-expressor' strategy with inhibitors of Dnmts and HDACs are underway. Thus, resensitization to biological agents such as retinoids, colony-stimulating factors and other differentiation inducers may be envisioned.

DNA Methylation↗
PubMed2004

Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin's lymphoma.

Epigenetic inactivation of RASSF1A, a putative tumor suppressor with proapoptotic activity, is frequently observed in a number of solid tumors, including a variety of epithelial cancers, but has not been described in hematopoietic tumors. We have analysed the expression and methylation status of RASSF1A in Hodgkin's lymphoma (HL)-derived cell lines, primary HL tumors and serum samples from HL patients. RASSF1A transcription was detectable in only 2/6 HL cell lines. Methylation-specific PCR and bisulfite genomic sequencing revealed that the RASSF1A promoter was hypermethylated in all four RASSF1A-nonexpressing cell lines. 5-aza-2'-deoxycytidine treatment resulted in demethylation of the promoter and RASSF1A expression in these lines. Hypermethylation of RASSF1A was also detected in 34/52 (65%) primary HL tumors and in 2/22 serum samples from these patients. Microdissection of Hodgkin/Reed-Sternberg (HRS) cells from several of these cases confirmed that the RASSF1A hypermethylation we detected in the analysis of whole tumor originated from the tumor cell population. Although hypermethylation of RASSF1A was detected in 5/6 non-Hodgkin's lymphoma (NHL)-derived cell lines, only rare primary NHL (1/10 of Burkitt's lymphoma, 1/12 of post-transplant lymphoma, 1/12 diffuse large B-cell lymphoma, 0/27 of nasal lymphoma, 0/8 follicular center cell lymphoma, 0/4 mantle cell lymphoma, 0/4 anaplastic large cell (Ki-1+) lymphoma, 0/2 MALT lymphoma) showed hypermethylation of the promoter. No methylation was detected in any of the 14 normal PBMC. These results point to an important role for epigenetic silencing of RASSF1A in the pathogenesis of HL. Inactivation of RASSF1A could be one mechanism by which HRS cells escape the apoptosis that should occur following nonproductive immunoglobulin gene rearrangements.

Apoptosis↗
PubMed2004

The candidate tumor suppressor gene BLU, located at the commonly deleted region 3p21.3, is an E2F-regulated, stress-responsive gene and inactivated by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma.

Loss of heterozygosity at 3p21 is common in various cancers including nasopharyngeal carcinoma (NPC). BLU is one of the candidate tumor suppressor genes (TSGs) in this region. Ectopic expression of BLU results in the inhibition of colony formation of cancer cells, suggesting that BLU is a tumor suppressor. We have identified a functional BLU promoter and found that it can be activated by environmental stresses such as heat shock, and is regulated by E2F. The promoter and first exon are located within a CpG island. BLU is highly expressed in testis and normal upper respiratory tract tissues including nasopharynx. However, in all seven NPC cell lines examined, BLU expression was downregulated and inversely correlated with promoter hypermethylation. Biallelic epigenetic inactivation of BLU was also observed in three cell lines. Hypermethylation was further detected in 19/29 (66%) of primary NPC tumors, but not in normal nasopharyngeal tissues. Treatment of NPC cell lines with 5-aza-2'-deoxycytidine activated BLU expression along with promoter demethylation. Although hypermethylation of RASSF1A, another TSG located immediately downstream of BLU, was detected in 20/27 (74%) of NPC tumors, no correlation between the hypermethylation of these two TSGs was observed (P=0.6334). In addition to methylation, homozygous deletion of BLU was found in 7/29 (24%) of tumors. Therefore, BLU is a stress-responsive gene, being disrupted in 83% (24/29) of NPC tumors by either epigenetic or genetic mechanisms. Our data are consistent with the interpretation that BLU is a TSG for NPC.

Alleles↗
PubMed2004

Genetic and epigenetic alterations of the APC gene in malignant melanoma.

High levels of beta-catenin and activating mutations in the beta-catenin gene (CTNNB1) have been demonstrated in malignant melanomas, implicating dysregulated Wnt signalling in the pathogenesis of this malignancy. We systematically examined melanoma cell lines for activating CTNNB1 mutations as well as genetic and epigenetic alterations of the adenomatous polyposis coli gene (APC), another key component of the Wnt signalling transduction pathway. Of 40 cell lines tested, one carried a truncating APC mutation and loss of the corresponding wild-type allele, and one carried a CTNNB1 missense mutation. Hypermethylation of APC promoter 1A was present in five of the cell lines (13%) and in nine of 54 melanoma biopsies (17%). Cells with truncating APC or activating CTNNB1 mutations showed increased transcription from endogenous and ectopic beta-catenin/T-cell factor (Tcf)-responsive target genes, consistent with the known effects of these alterations on beta-catenin stability and Tcf transactivation. In contrast, cell lines with APC promoter 1A hypermethylation did not show increased Wnt signalling, probably due to residual APC activity expressed from promoter 1B. Suppression of APC transcripts in melanoma cells by stable expression of short hairpin RNAs led to a Wnt signalling-independent increase in cell proliferation, but also reduced the invasive growth in collagen type I. Collectively, our data suggest that the tumour-suppressive function of APC in melanocytic cells is dose dependent. We propose that epigenetic silencing of promoter 1A may contribute to the development of malignant melanoma by reducing the expression of APC to a level that promotes cell proliferation without compromising the invasive capacity.

Adenomatous Polyposis Coli Protein↗
PubMed2004

Epigenetic gene silencing by Runx proteins.

Runx family proteins have the potential for either activating or suppressing gene expression in a context-dependent manner. There are several mechanisms by which transcriptional repression can occur. A wide range of locus inactivation, that is often called gene silencing, is thought to be achieved by chromatin modifications. Recently, Runx family proteins were found to have an essential role in either temporal transcriptional repression or irreversible epigenetic silencing at the CD4 locus through binding to a CD4 silencer at different stages of development. These findings link Runx function to epigenetic gene regulation, and shed new light on the mechanisms by which Runx represses target gene expression.

Animals↗
PubMed2005

Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma.

Using microarrays, we have screened for genes reactivated by drugs that modify epigenetic mechanisms in pancreatic cancer cells. One of the genes identified was tissue factor pathway inhibitor 2 (TFPI-2), which encodes for a broad-spectrum serine proteinase inhibitor that negatively regulates the extracellular matrix degradation, an essential step in tumor invasion and metastasis. We therefore investigated the expression and methylation patterns of the TFPI-2 gene in pancreatic adenocarcinoma, and determined its role in tumor growth and invasion. In contrast to its abundant expression in normal pancreas, TFPI-2 mRNA was undetectable in a high fraction of pancreatic cancer cell lines and in primary pancreatic ductal neoplasms (IPMNs). Loss of TFPI-2 expression was associated with aberrant hypermethylation of its promoter CpG island. Treatment with the phorbol ester (PMA), known to stimulate the TFPI-2 promoter activity, augmented the TFPI-2 expression in cell lines with unmethylated or partially methylated TFPI-2, but failed to induce the expression in cell lines that harbored fully methylated TFPI-2. Aberrant methylation of TFPI-2 was also detected in 73% (102/140) of pancreatic cancer xenografts and primary pancreatic adenocarcinomas, was more likely in older patients with pancreatic cancer, and significantly correlated with progression of IPMNs (P=0.0002). Restored expression of the TFPI-2 gene in nonexpressing pancreatic cancer cells resulted in marked suppression in their proliferation, migration, and invasive potential in vitro. We thus conclude that epigenetic inactivation of TFPI-2 is a common mechanism that contributes to the aggressive phenotype of pancreatic ductal adenocarcinoma.

Adenocarcinoma↗
PubMed2005

Epigenetic mechanisms affect mutant p53 transgene expression in WAP-mutp53 transgenic mice.

We describe the construction and phenotypic characterization of 23 whey acidic protein (WAP)-mutp53 transgenic mouse lines. The mutp53-expressing lines showed a mosaic expression pattern for the transgenes, leading to a heterogeneous yet mouse line-specific expression pattern for mutp53 upon induction. Only few lines were obtained, in which the majority of the induced mammary epithelial cells expressed the mutp53 transgene, most of the transgenic lines did not express mutp53, or expressed the transgene in less than 2% of the induced mammary epithelial cells. Hormone requirements for mutp53 transgene expression from the WAP-promoter differed in high and low expressing lines, being low in high expressing lines, and even lower in multiparous mutp53 mice, where persistent expression of the transgene occurred. Repeated induction of mutp53 expression through repeated parturition resulted in the formation of expanding mutp53-expressing foci within the mammary alveolar epithelium. The data suggest that epigenetic mechanisms play a role in modulating the expression of the mutp53 transgene. To support this idea, we crossed a nonexpressing WAP-mutp53 line with a strongly SV40 T-antigen-expressing WAP-T mouse line. In the bitransgenic mice, T-antigen-induced chromatin remodeling led to re-expression of epigenetically silenced mutp53 transgene(s). In these mice, mutp53 expression was much more variable compared to SV40 T-antigen expression, and seemed to depend on the coexpression of SV40 T-antigen. Mutp53 expression in this system thus resembles the situation in many human tumors, where one can observe a heterogeneous expression of mutp53, despite a homogeneous distribution of the p53 mutation in the tumor cells.

Animals↗
PubMed2005

Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach.

Human retinoblastoma occurs in two forms (familial and sporadic) both due to biallelic mutation of the RB1/p105 gene even if its loss is insufficient for malignancy. We have recently reported that loss of expression of the retinoblastoma-related protein pRb2/p130 correlates with low apoptotic index, suggesting that RB2/p130 gene could be involved in retinoblastoma. Mutational analysis of RB2/p130 in primary tumors showed a tight correlation between Exon 1 mutations and pRb2/p130 expression level in sporadic retinoblastoma. These mutations are located within a CpG-enriched region prone to de novo methylation. Analysis of RB2/p130 methylation status revealed that epigenetic events, most probably consequent to the Exon 1 mutations, determined the observed phenotype. Treatment of Weri-Rb1 cell line by 5-Aza-dC induced an increase in expression level of pRb2/p130, E2F1, p73 and p53. Overall, our results highlight a crucial role of epigenetic events in sporadic retinoblastoma, which opens a perspective for new therapeutic approaches.

Azacitidine↗
PubMed2005

Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs.

The mechanism of action of chemotherapeutic drugs and their ability to induce multidrug resistance (MDR) are of relevance to cancer treatment. Overexpression of P-glycoprotein (Pgp) encoded by the MDR1 gene following chemotherapy can severely limit the efficacy of anticancer agents; however, the manner by which cells acquire high levels of Pgp has not been defined. Herein, we demonstrate that chemotherapeutic drugs induce specific epigenetic modifications at the MDR1 locus, concomitant with MDR1 upregulation mediated by transcriptional activation, and a potential post-transcriptional component. We have established that the mechanisms are not mutually exclusive and are dependent on the methylation state of the MDR1 promoter. MDR1 upregulation did not result in further changes to the CpG methylation profile. However, dramatic changes in the temporal and spatial patterning of histone modifications occurred within the 5' hypomethylated region of MDR1, directly correlating with MDR1 upregulation. Specifically, drug-induced upregulation of MDR1 was associated with increases in H3 acetylation and induction of methylated H3K4 within discrete regions of the MDR1 locus. Our results demonstrate that chemotherapeutic drugs can actively induce epigenetic changes within the MDR1 promoter, and enhance the MDR phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗