104 results found
Lo Nigro C, Gasco M, Vivenza D, et al., 2011, Genetic and epigenetic determinants of outcome in locally advanced head-and-neck cancer, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Allen M, Syed N, Luong F, et al., 2011, Epigenetic silencing of argininosuccinate synthetase renders human bladder cancer cells sensitive to pegylated arginine deiminase, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Syed N, O'Neilli K, Hughes M, et al., 2011, Transcriptional silencing disrupts two levels of arginine biosynthesis in glioblastoma multiforme: a novel, targeted therapeutic strategy for high grade gliomas, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Syed N, 2011, The arginine biosynthetic pathway is targeted at two levels in glioblastoma multiforme brain tumours by epigenetic changes in arginino-succinate (ASS1) and arginino-succinate lyase (ASL):implications for targeted therapy, Journal of Clinical Investigation
Hatzimichael E, Dasoula A, Benetatos L, et al., 2010, Study of specific genetic and epigenetic variables in multiple myeloma, LEUKEMIA & LYMPHOMA, Vol: 51, Pages: 2270-2274, ISSN: 1042-8194
Lo Nigro C, Syed N, Lattanzio L, et al., 2010, P3H COLLAGEN PROLYL HYDROXYLASES ARE TISSUE SELECTIVE TUMOUR SUPPRESSORS, 35th European-Society-for-Medical-Oncology (ESMO) Congress, Publisher: OXFORD UNIV PRESS, Pages: 42-43, ISSN: 0923-7534
Hannigan A, Smith P, Kalna G, et al., 2010, Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter., J Clin Invest, Vol: 120, Pages: 2842-2857
The cytokine TGF-beta acts as a tumor suppressor in normal epithelial cells and during the early stages of tumorigenesis. During malignant progression, cancer cells can switch their response to TGF-beta and use this cytokine as a potent oncogenic factor; however, the mechanistic basis for this is poorly understood. Here we demonstrate that downregulation of disabled homolog 2 (DAB2) gene expression via promoter methylation frequently occurs in human squamous cell carcinomas (SCCs) and acts as an independent predictor of metastasis and poor prognosis. Retrospective microarray analysis in an independent data set indicated that low levels of DAB2 and high levels of TGFB2 expression correlate with poor prognosis. Immunohistochemistry, reexpression, genetic knockout, and RNAi silencing studies demonstrated that downregulation of DAB2 expression modulated the TGF-beta/Smad pathway. Simultaneously, DAB2 downregulation abrogated TGF-beta tumor suppressor function, while enabling TGF-beta tumor-promoting activities. Downregulation of DAB2 blocked TGF-beta-mediated inhibition of cell proliferation and migration and enabled TGF-beta to promote cell motility, anchorage-independent growth, and tumor growth in vivo. Our data indicate that DAB2 acts as a tumor suppressor by dictating tumor cell TGF-beta responses, identify a biomarker for SCC progression, and suggest a means to stratify patients with advanced SCC who may benefit clinically from anti-TGF-beta therapies.
Lee S, Syed N, Taylor J, et al., 2010, DUSP16 is an epigenetically regulated determinant of JNK signalling in Burkitt's lymphoma, BRITISH JOURNAL OF CANCER, Vol: 103, Pages: 265-274, ISSN: 0007-0920
Lee S, syed N, Taylor J, et al., 2010, DUSP16 is an epigenetically regulated determinant of JNK signalling in Burkitt's lymphoma, British Journal of Cancer, Vol: 103
BACKGROUNDThe mitogen-activated protein kinase (MAPK) phosphatases or dual specificity phosphatases (DUSPs) are a family of proteins that catalyse the inactivation of MAPK in eukaryotic cells. Little is known of the expression, regulation or function of the DUSPs in human neoplasia.METHODSWe used RT-PCR and quantitative PCR (qPCR) to examine the expression of DUSP16 mRNA. The methylation in the DUSP16 CpG island was analysed using bisulphite sequencing and methylation-specific PCR. The activation of MAPK was determined using western blotting with phospho-specific antibodies for extra-cellular signal-related kinase (ERK), p38 and c-Jun N-terminal kinase (JNK). The proliferation of cell lines was assessed using the CellTiter 96 Aqueous One assay.RESULTSThe expression of DUSP16, which inactivates MAPK, is subject to methylation-dependent transcriptional silencing in Burkitt's Lymphoma (BL) cell lines and in primary BL. The silencing is associated with aberrant methylation in the CpG island in the 5' regulatory sequences of the gene blocking its constitutive expression. In contrast to BL, the CpG island of DUSP16 is unmethylated in other non-Hodgkin's lymphomas (NHLs) and epithelial malignancies. In BL cell lines, neither constitutive nor inducible ERK or p38 activity varied significantly with DUSP16 status. However, activation of JNK was increased in lines with DUSP16 methylation. Furthermore, methylation in the DUSP16 CpG island blocked transcriptional induction of DUSP16, thereby abrogating a normal physiological negative feedback loop that limits JNK activity, and conferred increased cellular sensitivity to agents, such as sorbitol and anthracycline chemotherapeutic agents that activate JNK.CONCLUSIONDUSP16 is a new epigenetically regulated determinant of JNK activation in BL.
Schmid P, Fleischmann C, Wischnewsky M, et al., 2010, Use of prolyl 3-hydroxylases (P3H) to predict endocrine sensitivity in primary breast cancer., JOURNAL OF CLINICAL ONCOLOGY, Vol: 28, ISSN: 0732-183X
Hatzimichael E, Dasoula A, Shah R, et al., 2010, The prolyl-hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia, EUROPEAN JOURNAL OF HAEMATOLOGY, Vol: 84, Pages: 47-51, ISSN: 0902-4441
Hatzimichael E, Crook T, 2010, The prolyl-hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia, European Journal of Haematology
Syed N, 2009, Deficiency of argininosuccinate synthetase expression confers sensitivity to arginine depletion with arginine deiminase in glioblastomas, AACR: Genetics and Biology of Brain Cancers
Despite aggressive radio-chemotherapy, the prognosis for patients with glioblastoma multiforme (GBM) remains poor. New agents are therefore required. The molecular mechanisms, which are key in the pathogenesis and progression of GBM are still poorly understood. A recent documented mutations of isocitrate dehydrogenase 1 and 2 in more than 70% of astrocytomas (Yah H, 2009) brought the attention on metabolism as a primary target in the development of novel treatment modalities for these tumours. Using de novo gene finding techniques and epigenetic profiling in human GBM cell lines and cultured explants of primary GBM, we observed frequent transcriptional silencing of the 2 most important enzymes of the arginine biosynthetic pathway: argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL). We observed that loss of expression of ASS1, as determined by RT-PCR and immunohistochemistry, confers arginine auxotrophy to GBM cell lines and primary tumour explants. This confers sensitivity to highly selective, dose-dependent killing of the cells by arginine deprivation due to either nutritional starvation or pharmacological depletion with pegylated arginine deiminase (ADI-PEG20, Polaris Pharmaceuticals, Inc., San Diego, CA, USA). We have further demonstrated on tumour tissue sections that 20% of de novo GBMs have little or no expression of ASS1 indicating that ASS1 expression tested by immunohistochemistry represents an excellent predictor of response to arginine deprivation with arginine deiminase treatment. These pharmacogenomic findings suggest that ASS1 negativity may serve as a biomarker to select a population sensitive to arginine depletion with ADI-PEG20. Further studies are warranted.
Dasoula A, Hatzimichael E, Dranitsaris G, et al., 2009, Snk/Plk2 CpG methylation in patients with multiple myeloma, 45th Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Dasoula A, Hatzimichael E, Dranitsaris G, et al., 2009, Snk/Plk2 CpG methylation in patients with multiple myeloma., J Clin Oncol, Vol: 27
e19532 Background: We previously showed that polo like kinase 2 (Snk/Plk2) is subject to methylation-dependent transcriptional silencing in a very high frequency in Burkitt lymphomas. Here, we have examined CpG methylation in Snk/Plk2 in a well-characterized series of multiple myeloma (MM) patients. METHODS: Bone marrow samples from individuals with MM were obtained at diagnosis and in 5 cases at disease progression as well. Genomic DNA was isolated and bisulphite modification was performed using commercially available kits. The methylation-specific polymerase chain reaction (MSP) was employed to study its methylation status. Control methylated and unmethylated genomic DNAs were included in each experiment. Ten bone marrow samples from individuals proven to have no haematological malignancy, served as negative controls. Logistic regression analyses were used to measure the association between gene methylation and the development of advanced disease (DS≥II), extramedullary disease, bone disease, anemia (Hb 10 mg/dl), serum albumin and beta 2 microglobulin levels. RESULTS: We analyzed the methylation of Snk/Plk2 in 45 cases of MM (24 male, 21 female, mean age 66.4 years ±12.4). Classical cytogenetic analysis was available in 30/45 patients and none of them was found to have chromosome 13 abnormalities. No sample from the control population was found methylated. The Snk/Plk2 promoter was found to be methylated in 27/45 patients (60%). Median survival of patients in whom the Snk/Plk2 CpG island was methylated was 7.1 years compared to a median survival of 8.8 years for unmethylated. However Snk/Plk2 methylation was not a predictor of excess mortality (HR=0.6, p=0.5), bone lytic lesions (OR=0.56, p=0.3), anemia (OR=0.5, p=0.3) or advanced stage as defined above (OR=0.8, p=0.7). CONCLUSIONS: Snk/Plk2 DNA Methylation is a frequent event in patients with multiple myeloma. There was no association between the methylation status of the gene and relevant clinical par
Bower M, Syed N, Papoudou-Bai A, et al., 2009, Methylation reversal in high-grade B lymphoma cell lines and novel epigenetic changes conserved between immunocompetent and HIV-positive hosts., J Clin Oncol, Vol: 27
8585 Background: Methylation-dependent transcriptional silencing is an important mechanism of tumour suppressor gene inactivation in neoplasia, including lymphoma. METHODS: Pharmacological "unmasking" of transcriptionally silenced genes in B lymphoma cell lines was achieved using 5' deazacytidine ± Trichostatin A and subsequent analysis of mRNA levels on micro-array. Candidate genes thus identified, were further analysed by qPCR, methylation-specific PCR (MSP) and bisulphite sequencing in B lymphoma cell lines and by MSP in clinical samples from sporadic (immunocompetent) (18 cases) and HIV-infected patients (14 cases). Samples in both patient groups were diffuse large B cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). Additionally, we analysed 8 cases of marginal zone lymphoma (MZL) from the immunocompetent group. RESULTS: We report the identification of 13 novel genes, not previously described in the literature, which are subject to methylation-dependent transcriptional silencing in high-grade lymphoma and whose expression can be reactivated by demethylating agents. The novel genes encode proteins involved in diverse functional classes and include pro-apoptotic members of the p53 pathway (Scotin), transcriptional regulators (Baz2B) and regulators of telomerase (Smrf2). The frequency of methylation in individual genes varied from approximately 10% to 75% in specific lymphoma subtypes, but was in general similar in high grade lymphomas in immunocompetent and HIV-infected hosts. CONCLUSIONS: Using pharmacological reversal of methylation, we have identified a number of genes, not previously implicated in human neoplasia, which are subject to transcriptional silencing in high-grade B lymphomas. The similar frequencies of methylation, observed in immunocompetent and HIV positive patients implies that the genes are fundamental in suppression of lymphomagenesis. Detection of methylated DNA of one or more of these genes may have utility as biomarkers of
Bower M, Syed N, Papoudou-Bai A, et al., 2009, Methylation reversal in high-grade B lymphoma cell lines and novel epigenetic changes conserved between immunocompetent and HIV-positive hosts, 45th Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Crook T, Syed N, Papoudou-Bai A, et al., 2009, Methylation reversal in high grade B lymphoma cell lines identifies novel epigenetic changes conserved between immunocompetent and HIV-positive hosts and others specific to HIV-associated lymphoma, HIV MEDICINE, Vol: 10, Pages: 5-5, ISSN: 1464-2662
Benetatos L, Bourantas KL, 2008, Methylation analysis of the von Hippel-Lindau gene in acute myeloid leukaemia and myelodysplastic syndromes, Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Lim SL, Green JA, 2008, Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer, British Journal of Cancer
Iorns E, Turner NC, Elliott R, et al., 2008, Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer., Cancer Cell, Vol: 13, Pages: 91-104, ISSN: 1535-6108
Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.
Gorrini C, Amati B, 2007, Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response, Nature
Smith P, Nicholson LJ, Syed N, et al., 2007, Epigenetic inactivation implies independent functions for insulin-like growth factor binding protein (IGFBP)-related protein 1 and the related IGFBPL1 in inhibiting breast cancer phenotypes., Clin Cancer Res, Vol: 13, Pages: 4061-4068, ISSN: 1078-0432
PURPOSE: To analyze epigenetic regulation of two related genes, insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) and IGFBPL1, and its significance as a determinant of clinical phenotypes in human breast cancer. EXPERIMENTAL DESIGN: We have investigated the expression and epigenetic regulation of IGFBP-rP1 and IGFBPL1 in human breast cancer cell lines and primary and metastatic carcinomas. RESULTS: Expression of IGFBP-rP1 and IGFBPL1 is down-regulated in breast cancer cell lines. Aberrant methylation in the CpG islands of each gene correlates well with loss of expression at the mRNA level. Analysis of methylation in DNA isolated from human primary breast tumors showed that methylation in either gene was associated with a worse overall survival (OS; P=0.008) and disease-free survival (DFS) following surgery (P=0.04) and worse DFS following adjuvant chemotherapy (P=0.01). Methylation of IGFBP-rP1 alone was associated with a trend toward decreased OS (P=0.10) and decreased DFS (P=0.25). Methylation in IGFBPL1 was clearly associated with worse OS (P=0.001) and DFS (P<0.0001). Methylation in either IGFBP-rP1 or IGFBPL1 was significantly associated with nodal disease (P<0.001). CONCLUSIONS: Expression of IGFBP-rP1 and IGFBPL1 is regulated by aberrant hypermethylation in breast cancer, implying that inactivation of these genes is involved in the pathogenesis of this malignancy. Analysis of methylation of these genes may have utility in prediction of clinical phenotypes, such as nodal disease and response to chemotherapy.
Crook T, Smith P, Syed N, et al., 2007, Conserved epigenetic changes in sporadic and HIV-associated high-grade B-cell lymphomas, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Bergamaschi D, Lu X, 2006, iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53, Nature Genetics
Crighton D, Wilkinson S, O'Prey J, et al., 2006, DRAM, a p53-induced modulator of autophagy, is critical for apoptosis, Cell, Vol: 126
Inactivation of cell death is a major step in tumor development, and p53, a tumor suppressor frequently mutated in cancer, is a critical mediator of cell death. While a role for p53 in apoptosis is well established, direct links to other pathways controlling cell death are unknown. Here we describe DRAM (damage-regulated autophagy modulator), a p53 target gene encoding a lysosomal protein that induces macroautophagy, as an effector of p53-mediated death. We show that p53 induces autophagy in a DRAM-dependent manner and, while overexpression of DRAM alone causes minimal cell death, DRAM is essential for p53-mediated apoptosis. Moreover, analysis of DRAM in primary tumors revealed frequent decreased expression often accompanied by retention of wild-type p53. Collectively therefore, these studies not only report a stress-induced regulator of autophagy but also highlight the relationship of DRAM and autophagy to p53 function and damage-induced programmed cell death.
Stebbing J, Bower M, Syed N, et al., 2006, Epigenetics: an emerging technology in the diagnosis and treatment of cancer, PHARMACOGENOMICS, Vol: 7, Pages: 747-757, ISSN: 1462-2416
Stebbing J, Crook T, 2006, Epigenetics: an emerging technology in the diagnosis and treatment of cancer, Pharmacogenomics
Gasco M, Syed N, Smith P, et al., 2006, A multi-gene algorithm as predictor of response to chemo-radiotherapy in head and neck cancer., J Clin Oncol, Vol: 24
10086 Background: Chemo-radiotherapy results in clinical cure for stage III/IV head and neck cancer in approximately 40% of cases, with significant treatment-associated morbidity and mortality. Molecular genetic factors predictive of treatment outcome would clearly be of value in selection of patients with highest probability of response. We have analysed the structure and epigenetic regulation of specific genes as possible predictors of outcome to chemo-radiotherapy. The genes analyzed were: p53 (single nucleotide polymorphism (SNP) and mutation), MDM2 (SNP), Chfr (methylation), CRABP1 (methylation). METHODS: 84 patients with locally advanced head and neck cancer receiving cisplatin-based chemo-radiotherapy were studied. SNP genotypes were determined by direct sequencing of DNA from normal tissue. Acquired mutations in p53 and aberrant methylation in the CpG islands of specific genes were analyzed by direct sequencing and methylation-specific PCR. RESULTS: There were 6 treatment-related deaths in 84 patients, all occurring in cases with germ-line haplotype p53 72 Arg/Arg, MDM2 309T/T. At the time of analysis, 39/84 (46%) patients had progressed or died, with median time to progression or death = 17.3 months. Complete response was more common in patients whose genetic/epigenetic profile was p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated, compared to the profile p53 72 Arg/Arg mutant, MDM2 309 T/T, Chfr unmethylated, CRABP1 unmethylated (91% vs 46%, log rank p = 0.002). Progression-free survival was significantly longer for patients with the profile p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated, compared to those with p53 72 Arg/Arg mutant, MDM2 309 T/T, Chfr unmethylated, CRABP1 unmethylated (% surviving progression-free at 2 years = 74% vs 36%, p = 0.001). Overall survival was significantly longer in patients with the profile p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated compared
Smith P, Syed N, Crook T, 2006, Epigenetic inactivation implies a tumor suppressor function in hematologic malignancies for Polo-like kinase 2 but not Polo-like kinase 3, Cell Cycle
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