M Esteller

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..As such drugs may serve as therapeutic agents for cancer, our findings support the use of HDAC2 mutational status in future pharmacogenetic treatment of these individuals...

..Our findings indicate that DNA methylation-associated silencing of tumor suppressor miRNAs contributes to the development of human cancer metastasis...

..However, other epigenetic mechanisms, such as modulation of chromatin structure or modifications of histones, may explain the lack of NKX3.1 expression, which is seen in most TGCTs and prostate cancer specimens...

..We compared the DNA methylation profiles of the cell lines with those of the primary tumors. Finally, we examined if the epigenetic changes were associated with known genetic markers and/or clinicopathological variables...

..Furthermore, promising studies using DNA demethylating agents and histone deacetylase inhibitors are underway to awake these dormant tumor-suppressor genes for a better treatment of the patient with a hematologic malignancy...

..In the very near future, the synergy of candidate gene approaches and large-scale epigenomic technologies, such as methyl-DIP, will yield the complete DNA hypermethylome of cancer cells...

..Finally, we must expect the development of new and more specific DNA demethylating agents that awake these methyl-dormant tumor suppressor genes and prove their therapeutic values. The expectations are high...

..These sites, among others, are the targets of DNA-demethylating agents, the promising chemotherapeutic drugs that are the focus of this article...

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..We need to make an ambitious step to understand the DNA methylation and histone changes underlying tumorigenesis. The launching of an International Human Epigenome Project should be the response to this necessity...

..These recent results underscore the importance of MGMT in basic and translational cancer research...

..It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches...

..Finally, dormant tumour suppressor genes can be reactivated by DNA demethylating drugs, with the aim of reversing the neoplastic phenotype. These are new avenues worth exploring in the fight against cancer...

..Here we briefly summarize present concepts of nuclear architecture and current data supporting a link between DNA methylation and the maintenance of large-scale nuclear organization...

..These results suggest a role for HDAC2 mutations in human tumorigenesis through the derepression of key genes from multiple cellular transformation pathways...

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..The latter is a member of this family of proteins and appears to play a role in reducing mutations at 5-methylcytosine. This review examines the contribution of methyl-CpG-binding proteins in the epigenetic pathway of cancer...

..Our data support a fundamental role for MBD proteins in the direct maintenance of transcriptional repression of tumor suppressors and identify new candidate genes for epigenetic disruption in cancer cells...

..All together, these findings suggest that tumor telomere length and integrity can be influenced by the epigenetic status of cancer cells...

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..Our results support an essential role for MBDs in gene silencing and, when combined with genomic strategies, their potential to 'catch' new hypermethylated genes in cancer...

..Thus, our results demonstrate the role of DNMT1 and DNMT3b in CpG island methylation associated silencing and the usefulness of genetic disruption strategies in searching for new hypermethylated loci...

..Aberrant patterns of epigenetic modifications will be, in a near future, crucial parameters in cancer diagnosis and prognosis...

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..Transcriptional silencing of tumor suppressor genes mediated by hypermethylation of promoter CpG islands is a hallmark of human tumors. We addressed the clinical relevance of promoter hypermethylation in neuroblastoma...

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..These findings highlight the importance of EXT1 epigenetic inactivation, leading to an abrogation of HS biosynthesis, in the processes of tumor onset and progression...

..In this review we present the models of how repressor complexes may modify chromatin structure and mediate silencing of tumour suppressor and DNA repair genes...

..Finally, we detected that hSpry2 promoter hypermethylation was associated with a significant decrease in the 5-year survival rate. These data suggest that hSpry2 could be important in lymphoid malignancies...

..The generation of novel aberrantly hypermethylated regions during cancer development and progression makes MBD proteins interesting targets for their biological and clinical implications...

..Basic and translational will both be needed in the near future to fully understand the mechanisms, roles and uses of CpG island hypermethylation in human cancer. The expectations are high...

..In the coming years we will come to realize more fully the relevance of this expected encounter between two forces-epigenetics and microRNAs-that are currently at the forefront of biology...

..029). The existence of these associations may provide another example of the interplay between genetic and epigenetic factors in the cancer cell...

..Our results indicate that MBDs have a great affinity in vivo for binding hypermethylated promoter CpG islands of tumor suppressor genes, with a specific profile of MBD occupancy that it is gene and tumor type specific...

..Our current data indicate that the use of HDAC inhibitors, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising for cancer patients...

..These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs...

..Taken together, our results underline Salermide's promise as an anticancer drug and provide evidence for the molecular mechanism through which Sirt1 is involved in human tumorigenesis...

..Aberrant patterns of epigenetic modifications will be, in a near future, crucial parameters in cancer diagnosis, prognosis and therapy...

..The identification of these connections has contributed not only to understanding how epigenetic deregulation occurs in cancer but also to developing novel therapies that can reverse epigenetic defects in cancer cells...

..These findings suggest a role for Dnmt1 as an epigenetic caretaker for the maintenance of nucleolar structure...

..Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells...

..The eruption of new technologies for the careful study of the DNA methylation patterns, and their genetic partners in accomplishing gene silencing, it may also provide us with new drugs for the epigenetic treatment of human tumors...

..These data support the general principle that the function of an individual protein is modulated through alternative splicing, and highlight a number of potential implications for Aiolos in normal and aberrant lymphocyte function...

..Our data indicate that DNMT1 activity, via maintenance of the appropriate histone H3 modifications, contributes to the preservation of the correct organization of large heterochromatic regions...

..These data suggest that TLE1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting critical differentiation and growth-suppressing pathways...

..These findings underline the importance of MGMT promoter hypermethylation in basic and translational cancer research...

..DKK-1 gene induction constitutes a novel mechanism of inhibition of Wnt signalling and antitumour action by 1,25(OH)2D3...

..Interestingly, the binding affinity of specific MBD proteins for methylated DNA fragments from naturally occurring sequences are affected by local methyl-CpG spacing...

..In addition, because epigenetic changes are reversible, enzymes involved in their maintenance stand as targets for a variety of compounds for therapy...

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..We discuss the biological significance of both groups of epigenetic modifications in terms of their relative contribution to ontogenic development, senescence, and cell proliferation...

..Most important, the TRBP impairment is associated with a destabilization of the DICER1 protein. These results provide, for a subset of human tumors, an explanation for the observed defects in the expression of mature miRNAs...

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..A thorough understanding of these alterations and their impact upon 3'UTR-directed posttranscriptional gene regulation will uncover promising new targets for therapeutic intervention...

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..In the present study, we discuss the implications of epigenetic alterations in the development and progression of SLE and how epigenetic drugs constitute a promising source of therapy to treat this disease...

..Our data provide a basis for a better use of human cancer cell lines in basic and translational research with respect to their DNA methylation environment...

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..We cannot rule out that other mechanisms, such as complete or partial deletions of the SMARCA4 gene, are contributing to the loss of the SMARCA4 protein in lung cancer...

..These results may open up possibilities for more customized treatments of human brain tumors...

..008, Fisher's exact test). Thus, the mutual exclusivity of the epigenetic and genetic alterations in the two genes of the Ras pathway suggests that they play a critical and cooperative role in human tumorigenesis...

..These results allow us to propose that the formation of transcription complexes with E2F6 may modify the functional status of PcG proteins in HSR cells...

..Our results provide new data of the underlying mechanisms of RTT and unveil novel targets of MeCP2-mediated gene repression...

..This fact suggests that somatic BRCA1 inactivation could modify the profile of tumor progression in most of the BRCAX cases...

..03) and death of disease (Kendall tau, P = 0.03; r = 0.19). Thus, EMP3 is a good candidate for being the long-sought tumor suppressor gene located at 19q13 in gliomas and neuroblastomas...

..However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required...

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..The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote beta-catenin accumulation in this tumor type...

..Thus, our findings demonstrate for the first time that LKB1/STK11 inactivation is a very common event and may be integrally involved in the development of sporadic lung adenocarcinoma...

..The association of SOX9 hypermethylation with tumour progression and clinical outcome suggests its relevant clinical implications at stratifying patients affected with bladder cancer...

..Recent studies have demonstrated the importance of PAX5 gene alterations in human cancer. Our results are the first to identify aberrant promoter methylation as a common mechanism for dysregulation of these genes in solid tumors...

..Our results suggest that EZH2 serves as a recruitment platform for DNA methyltransferases, thus highlighting a previously unrecognized direct connection between two key epigenetic repression systems...

..Overall, our data support the hypothesis that multiple genes are targeted, either directly or indirectly, by DNA hypermethylation during melanoma progression...

..Finally, the frequency of GSTP1 aberrant methylation in diffuse large B-cell lymphoma prompts studies aimed at verifying the prognostic impact of this epigenetic lesion in these lymphomas...

..Epigenetic disruption of CRBP1 is a common event in human cancer that may have important implications for cancer prevention and treatment using retinoids...

..The high number of chromosomal imbalances in tumors with complete absence of CHK2 protein suggests a role of this gene in chromosomal instability in human lymphomas...

..Silencing of the SOCS-1 gene may impair negative regulation of the Jak/STAT pathway and therefore result in greater responsiveness to cytokines, thus supporting survival and expansion of MM cells...

..These results underpin the epigenetic inactivation of the chromating remodeling factor CHD5 as one contributor for the aberrant structural changes of chromatin throughout the genome of the cancer cell...

..CONCLUSION: MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide...

..Selection for silencing of both upstream transcription factors and their target genes in GI cancers could indicate that epigenetic silencing of the involved genes provides a summated contribution to tumor progression...

..We conclude that HIC1 is a candidate tumor-suppressor gene for which loss of function in both mouse and human cancers is associated only with epigenetic modifications...

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