bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4880: CASZ1, a neuroblastoma tumor suppressor gene, is epigenetically silenced by EZH2
Authors: Wang Chunxi , Woo Chanwook , Liu Zhihui , Wei Jun , Song Young , Wang Lifeng , Khan Javed , Ge Kai , Thiele Carol J. 
Published: February 2011

Abstract
Casz1 is a C2H2 Zn-finger transcriptional factor that localizes to a region of LOH on Chr1p36.22 in tumors of Neuroblastoma patients who have a poor prognosis. Moreover, high CASZ1 expression is found in tumors of patients with a good prognosis while tumors from patients with a poor prognosis express low levels of CASZ1 (58 patients, p= 2.07×10-6). Studies indicate that CASZ1 functions as a tumor suppressor gene. Our finding that treatment of NB cells with HDAC inhibitors results in a 10-fold increase in CASZ1 expression suggests that epigenetic silencing contributes to the functional loss of CASZ1 expression from the remaining Chr1p36.22 allele. In studying the mechanism of CASZ1 epigenetic silencing, we found a bivalent chromatin modification region around the CASZ1 Transcription Start Site (TSS) that contains both a H3K27 methylation mark as well as an H3K4 methylation mark. The H3K27 methylation is thought to be a gene repressive marker, which is catalyzed by Polycomb repressor complex 2 (PRC2) proteins. PRC2 contains three core components, EZH2, EED and SUZ12, in which EZH2 (enhancer of zeste 2) is a methyltransferase catalyzing H3K27 methylation. Using Chromatin Immunoprecipitation (ChIP) we identified a 5-fold decrease in binding of EZH2, EED and SUZ12 to the bivalent region after HDAC inhibitor treatment. Consistent with decreased PRC2 binding is the finding of decreased tri-methylation of H3K27 and an increase in H3K4me3, a histone mark associated with transcriptionally active genes. The changes in histone modifications are associated with the activation of the CASZ1 gene. RNA silencing of EZH2 also leads to increases in CASZ1 expression. Consistent with this, CASZ1 expression is also up-regulated (3- fold) in EZH2 knockout MEFs compared to EZH2 wild type MEFs. This indicates that CASZ1 expression on the remaining allele is silenced by epigenetic modifications mediated by EZH2. High expression of EZH2 and EED are also found in tumor samples of neuroblastoma patients with a poor prognosis (58 patients, p=2.6×10-3 for EED and p=5.87×10-4 for EZH2). This is consistent with a model in which aberrant epigenetic gene silencing of the tumor suppressor gene CASZ1 contributes to neuroblastoma tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4880.
Abstract 4881: Polycomb protein EZH2 activates Wnt/β-catenin signaling to promote hepatocellular carcinoma development
Authors: Cheng Alfred S. , Lau Suki , Chen Yangchao , Kondo Yutaka , Li May , Feng Hai , Ching Arthur , Cheung Paul , Wong Kenneth , Jin Hongchuan , Choy Richard , Yu Jun , To Ka F. , Wong Nathalie , Huang Tim , Sung Joseph J. 
Published: February 2011

Abstract
Aberrant activation of the canonical Wnt pathway due to accumulation of
β-catenin occurs in approximately 70% of hepatocellular carcinomas (HCCs) and contributes to their initiation, development and progression. Genetic mutations in the components of this pathway account for only a subset of HCCs with β-catenin accumulation, suggesting that an alternative mechanism for Wnt/β-catenin activation is prevailing. Enhancer of zeste homolog 2 (EZH2) is known to promote tumorigenesis by down-regulating tumor-suppressor genes; however, whether EZH2 regulates oncogenic pathways is unclear. Using chromatin immunoprecipitation microarray, we uncovered 12 Wnt/β-catenin signal antagonists whose promoters were concordantly occupied by EZH2 and repressive histone modifications in hepatocellular HCC cells. EZH2 over-expressed in 42% (75/179) of human HCCs and significantly associated with β-catenin accumulation. Concomitant inhibition of EZH2 and histone deacetylase transcriptionally activated Wnt/β-catenin signal antagonists, suppressed T-cell factor-dependent transcriptional activity and down-regulated β-catenin transcriptional targets in HCC cells. Conversely, ectopic EZH2 over-expression in nontumorigenic hepatocytes increased cellular proliferation in a β-catenin-dependent manner and promoted tumorigenicity. This study uncovers an EZH2-mediated epigenetic mechanism that leads to Wnt/β-catenin signaling dyregulation in human HCC and suggests that therapeutic interventions targeting EZH2 may confer a clinical benefit in β-catenin-driven malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4881.
Abstract 4883: Differences in epigenetic patterns of HOX genes in normal lung and Non-small cell lung cancer
Authors: Lee Borum , Chun Sung-Min , Jin Min-Young , Jang Se Jin 
Published: February 2011

Abstract
HOX genes have determinative roles in cell fate during embryogenesis and adult cellular differentiation. Their dysregulation has been implicated in many human cancers. Loss of or de novo expression of the genes by methylation abnormality are also reported in non-small cell lung cancer (NSCLC). In this study, we screened the expression profiles of the HOX D genes in normal lung tissues, a bronchial epithelial cell line, 9 NSCLC cell lines and 10 normal-tumor pairs of NSCLC tissues and compared epigenetic patterns of the genes by Quantitative Real-Time PCR, Dual-Specific Bisulfite PCR (DSBP) and ChIP-on-chip assay. We showed frequent cancer specific de novo expression of HOX D9, D11, and D13 genes in NSCLC tissues and cells in contrast to normal lung tissues. In methylation assay, unexpectedly, the genes are frequently hypermethylated in cancerous samples but show low level of methylation in normal tissues. In ChIP-on-chip assay, we observed that normal tissues show repressive or bivalent histone modification pattern characterized by high level of H3K27me3 and low level of H4K20me3 and H4K16ac at the up-stream region of the genes. In contrast, cancer tissues showed permissive or active histone modification patterns at the region characterized by low level of H3K27me3 and high level of H4K20me3 and H4K16ac. The results suggest that normal epigenetic state of the genes in lung tissue could be defined as bivalent histone modification pattern, no DNA methylation and no gene expression. In lung cancer, epigenetic state of the genes are dysregulated to permissive histone modification pattern, DNA hypermethylation and de novo expression of the genes. (This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea. (A084921), This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea. (A062254))
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4883.
Abstract 4884: Polyamine analogues in combination with DFMO inhibits lysine-specific demethylase 1 and induces re-expression of aberrantly silenced genes
Authors: Wu Yu , Marton Laurence J. , Woster Patrick M. , Casero Robert A. 
Published: February 2011

Abstract
Epigenetic gene silencing is an important mechanism for the loss of gene expression in cancer. Abnormal DNA CpG island hypermethylation and altered patterns of histone modifications are involved in aberrant silencing of tumor suppressor gene. The flavin-dependent lysine-specific demethylase 1 (LSD1) is the first enzyme identified to specifically demethylate Lysine 4 of histone H3. Methylation of H3K4 is an important mark associated with active chromatin transcription. The FAD-binding amine oxidase domain of LSD1 has considerable sequence homology to two polyamine oxidases SMO (spermine oxidase) and APAO (acetylpolyamine oxidase). Our laboratory has identified long chain polyamine analogues, named oligoamines, act as inhibitors of LSD1. Here we report the synergistic effects of specific oligoamines in combination treatment with 2-difluoromethylornithine (DFMO) in human colorectal cancer cells. DFMO is an inhibitor of ornithine decarboxylase (ODC), which is a rate-limiting enzyme to generate putrescine. Reducing the level of putrescine leads to accumulation of decarboxylated S-adenosylmethionine (dcSAM) and could subsequently result in alteration of DNA methyltransferase activity and changes in DNA methylation. In addition, DFMO treatment is known to increases uptake of circulating polyamines. Exposure of colorectal tumor cells to oligoamines and DFMO results in a synergistic global increase of H3K4me2 and induction of re-expression of aberrantly silenced genes including the secreted frizzled-related protein 2 (SFRP2) gene, which encodes Wnt signaling pathway antagonist and plays an anti-tumorigenesis role in colorectal cancer. Chromatin immunoprecipitation analysis indicates that the re-expression of SFRP2 is associated with increased H3K4me2 active marks at the gene promoter. The combination of LSD1-inhibiting oligoamines and DFMO represents a highly valuable and novel approach to epigenetic therapy of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4884.
Abstract 4887: Genetic analyses of chromatin remodelers in cancer
Authors: Riudalbas Laia S. , Melo Sónia A. , Mestres Anna Portela , Esteller Manel 
Published: February 2011

Abstract
Genetic analyses of chromatin remodelers in cancer
Laia S. Riudalbas1, Sónia A. Melo, Anna Portela & Manel Esteller.
1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet, Barcelona, Catalonia, Spain
Chromatin remodelers are ATP dependent proteins that enable dynamic access to packaged DNA and tailor nucleosome composition in chromosomal regions. These protein complexes have been shown to regulate a wide range of cellular processes, including transcription regulation, DNA-damage response and DNA replication. Being that some components of this remodeler machinery were already characterized as tumor suppressor genes and/or oncogenic, we can hypothesize that the dysregulation of any of these molecules in tumor cells with microsatellite instability (MSI+), that show a higher rate of insertions and deletions, can lead to neoplastic transformation. For that we decided to screen all the exonic mononucleotide repeats of some of the most important chromatin remodelers with ATPase activity in colorectal, gastric and endometrial cancer cell lines, on the search for frameshift mutations that could alter protein function. We have mainly analyzed the catalytic subunits of remodeling complexes because any alteration of these crucial proteins could drive into a tumorigenic process. Until now no alteration was found in the cancer cell lines studied. This could be underscoring the importance of these genes to normal cellular functioning being that their disruption could impair cell viability.
This work was supported by Grants SAF2007-00027-65134, FIS PI08-0517, Consolider CSD2006-49, and CANCERDIP FP7-200620. L.S.R. is a research fellow of FIS - Instituto de Salud Carlos III, FI09/00218.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4887.
Abstract 4888: The effect of chromatin structure in regulation of telomere length in telomerase negative ALT cells
Authors: Jung A Ra , Kim Hye Ryun , Oh Bong-Kyeong , Jeung Hei-Cheul , Chung Hyun Cheol , Rha Sun Young 
Published: February 2011

Abstract
Telomeres are DNA-protein complexes at the ends of linear eukaryotic chromosomes and composed of tandem repeats of a TTAGGG sequence ending in a 3′ single-stranded overhang, or the G-strand overhang. And telomeres confer chromosomal stability protecting chromosome ends. Most immortalized human cell lines maintain and extend their telomere by activating telomerase. A small number of cells maintain and extend their telomere lengths without telomerase by homologous recombination of telomeres and this mechanism is called as alternative lengthening of telomere (ALT). There are many factors involved in telomere regulation. Recently, it has been known that chromatin structure is closely related to regulation of telomere length. Maintaining telomere length is important process in tumorigenesis and it has been suggested that telomeres are important target for cancer therapy. However, in ALT cells the effect of chromatin structure on regulation of telomere length is not understood. In this study, we induced change of chromatin structure by treating Trichostatin A (TSA), Histone deacetylase inhibitor, in ALT cells. Then, we measured APBs (ALT associated PML bodies) patterns, T-SCE (Telomere Sister Chromatid Exchange) frequency and telomere lengths. APBs patterns were analyzed by FISH (Fluorescence in situ hybridization) combined IF (Immunofluorescence staining). We compared the number of APBs in ALT cells with or without TSA. In GM 847 (ALT cell), APBs positive cells were found to be more frequent in GM 847 with TSA (63/100) compared to GM 847 without TSA (30/100) (p&lt;0.001). A similar result was found in other ALT cell line, WI38-VA13. APB positive cells were more frequent in WI38-VA13 with TSA (38/100) compare to WI38-VA13 without TSA (18/100), (p&lt;0.001). T-SCE frequency was determined by CO-FISH (Chromosome Orientation-FISH). Increse of T-SCE frequency was found in GM 847 with TSA (262/1026, 25.5%) compared to GM 847 without TSA (215/1026, 20.9%), (p&lt;0.001). Telomere length was determined by telomere-FISH. Decrease of telomere length was found in GM 847 with TSA (telomere intensity mean 25.11%) compared to GM 847 without TSA (telomere intensity mean 29.8%), (p&lt;0.001). This study demonstrated a close association between chromatin structure and telomere recombination in ALT cells and this result might provide insight into the mechanism of regulation of telomere length in telomerase-negative cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4888.
Abstract 4893: EGFR signaling controls the chromatin binding status of BMI1 through a CK2/PP1 phosphorylation/dephosphorylation pathway and affects astrocytoma proliferation and neural stem cell differentiation
Authors: Hawes Jessica , Tuskan Robert , Akagi Keiko , Reilly Karlyne 
Published: February 2011

Abstract
Studies of brain tumors demonstrate the importance of a rare tumor cell population with the capability of regenerating tumors upon transplantation. These cancer stem cells (CSC) are believed to be more resistant to therapy than the bulk of brain tumor cells. Studies in mouse brain tumor models demonstrate that neural stem cells (NSC) can be an important initiating cell type for brain tumors, but it is unclear what is the relationship between NSC and CSC. EGF is a critical growth factor for NSC maintenance in culture and EGFR signaling is upregulated in glioblastoma. Similarly, the chromatin modulator BMI1 is necessary for NSC maintenance, and has been implicated in glioblastoma. We present studies linking cell surface EGF signaling and nuclear BMI1 chromatin binding. We demonstrate that BMI1 is specifically phosphorylated by EGFR signaling using EGF and TGFα, but not by many other oncogenic signaling ligands tested. We have identified three amino acids encompassing the phosphorylation site in response to EGFR signaling, and show that CK2 and PP1 are necessary for control of BMI1 phosphorylation. This phosphorylation alters the chromatin binding state of BMI1 and transcriptional regulation in astrocytoma cells. Interestingly we find that BMI1 can alter transcriptional profiles in both EGF-dependent and independent ways, suggesting that different signaling pathways could have specific effects on changing the BMI1-dependent epigenetic state of subsets of genes. Furthermore, EGF-induced phosphorylation of BMI1 is important for astrocytoma growth in vitro and in vivo, as well as maintenance of NSC.
Our data link signals outside the cell to the nucleus important for NSC maintenance and astrocytoma proliferation. These data represent a common pathway in NSC and tumor cells that may explain the importance of EGF signaling for NSC maintenance and gliomagenesis, and suggest a novel downstream pathway (CK2/PP1) involved in these processes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4893.
Abstract 4896: The detection and analysis of epigenetic and genetic changes in ovarian tumor tissue
Authors: Poulin Matthew , Xu Jessica , Yan Liying 
Published: February 2011

Abstract
Human ovarian cancer is the fifth leading cause of cancer-related deaths. Most ovarian cancers are ovarian epithelial carcinomas or malignant germ cell tumors. Similar to other cancers, the early diagnosis of ovarian cancer is critical for treatment of the disease and the better chance for recovery. If diagnosed and treated early when the cancer is confined to the ovary, the 5-year survival rate is over 90%. Many studies involving various types of human cancers proved and aberrant miRNA expression occurs in many cancers, even at the early stage of the diseases, indicating its causative role. We have analyzed 10 ovarian tumors and their associated normal tissue, and two ovarian cancer cell lines, with methylation assays for over 25 different cancer related genes (p16, ESR, BRCA1, Rassf1, RAR beta, ECAD, etc.) including several miRNA genes. Global methylation assays show the ovarian tumors to be hypomethylated compared to the corresponding normal tissue. Several of the miRNA genes we have analyzed in ovarian tumor tissue show statistically changes in methylation pattern within their promoters compared with adjacent normal tissue. ANOVA analysis shows a variance with a p value of 0.00001. Expression analysis will be performed to correlate with the methylation data. Additionally, an extensive SNP analysis will be conducted on these tissues in order to establish specific screening parameters that will aid in early detection of this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4896.
Abstract 4907: Methylated cell-free DNA in plasma as an early biomarker of pancreatic cancer
Authors: Mangold Kathy A. , Amick Ashley , Wang Vivien , Regner MaryAnn , Krafft Catherine , Du Hongyan , Brand Randall E. , Kaul Karen L. 
Published: February 2011

Abstract
Background: Presently there is an urgent need for better biomarkers for early pancreatic cancer (PaCa) diagnosis. Hypermethylation of several genes is known to correlate with presence of neoplasia in pancreatic tissue, and tumor DNA is known to be present in bodily fluids. With this background, we wanted to develop and validate a panel of methylated gene markers that would provide clinically relevant information when applied to plasma from those undergoing diagnostic procedures for pancreatic cancer.
Methods: Cell-free DNA was extracted from plasma obtained from 11 PaCa patients, 15 pancreatitis patients and 15 unaffected age-matched controls using either the automated EZ-1 (Qiagen, Valencia, CA) or the manual Charge Switch (Invitrogen, Carlsbad, CA) methods. The DNA was bisulfite treated using EZ DNA Methylation-Gold (Zymo Research, Orange, CA) then analyzed using a panel of quantitative real-time PCR assays to discriminate the methylated C or T that exists after bisulfite conversion, and normalizing the signal to the amplification level of a housekeeping gene (Col2A) to assess methylation of status of 13 genes known to be differentially methylated in pancreatic tissues. Several different combinations of 6 methylated gene markers (3-OST-2, ARF/p14, FOXE1, CDKN2/p16, ppENK, and RASSF1A) showed good discrimination between the 3 groups of patients to warrant further study with an additional 53 plasma specimens (from 21 PaCa patients, 17 pancreatitis patients, and 15 unaffected controls). Receiver operator curves were generated to examine the predictive probability between marker methylation and disease, and reliability of the regression model was evaluated by using the Hosmer-Leme show goodness-of-fit test.
Results: Statistical analysis of the 6 methylated gene markers for all 94 plasma specimens yielded an AUC of 0.638 (95% CI: 0.50-0.78) to differentiate PaCa from pancreatitis, and the goodness-of-fit for the model was good (p=0.697).
Conclusions: Cell-free DNA extracted from plasma is an appropriate sample for the study of gene methylation in PaCa. We utilized real-time assays to detect methylation in 6 target genes and found a good correlation between the methylation status of genes and the presence of PaCa. Further studies are needed to define the clinical utility of this approach. Funding was provided by a grant from the American Cancer Society - Illinois Division (#07-06) and by funds from the Department of Pathology and Laboratory Medicine at NorthShore.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4907.