bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4978: The C/EBPbeta isoform, liver-enriched inhibitory protein (LIP) induces cell death in breast cancer cell lines
Authors: Abreu Maria M. , Sealy Linda 
Published: August 2012

Abstract
C/EBPbeta is a member of a family of basic-leucine zipper transcription factors. It has been shown to be a key regulator of growth and differentiation in the mammary gland. There are three different protein isoforms of C/EBPbeta. C/EBPbeta-1 and -2 are transactivators, and differ by just 23 N-terminal amino acids present in beta-1 only. C/EBPbeta-3 (LIP) lacks the transactivation domain and represses transcription. Here, we report that LIP expression stimulates autophagy and induces cell death in breast cancer cell lines. Overexpression of LIP is incompatible with cell growth and when cell cycle analysis was performed in the LIP-MDA-MB-231 breast cancer cell line, a DNA profile of cells undergoing apoptosis was not observed. Instead, LIP expressing cells appeared to have large autophagic vesicles when examined via electron microscopy. Autophagy is an evolutionarily conserved cellular process responsible for self-cannabalization through a lysosomal degradation pathway. Autophagy was further assessed in LIP expressing and control breast cancer cells by monitoring the development of acidic vesicular organelles and conversion of LC3 from the cytoplasmic form to the autophagosome form. LIP expression leads to an increase in acidic vesicles. In addition, activation of LC3 was detected in LIP expressing cells by immunoblot analysis and immunofluorescence studies. Interestingly, we find that LIP expression not only leads to massive and rapid cell death in the MDA-MB-468 breast cancer cell line, but cell cycle profiling reveals a dramatic increase in DNA content in LIP expressing cells. We present data that the induction of autophagy appears to accompany or possibly follow the engulfment of neighboring cells by the LIP expressing cells. Recently, there have been reports of different cell death processes that occur due to cell internalization. LIP overexpression may be one important factor that is driving cell engulfment resulting in cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4978. doi:1538-7445.AM2012-4978
Abstract 4989: Selective inhibitors of the inositol-requiring enzyme 1 kinase domain
Authors: Griffin Carly , Abibi Ayome , Subramaniam Ratheesh , Zaidi Hassan S. , Marcellus Richard , Poda Gennadiy , Prakesch Michael , Uehling David , Canny Marella , Chiovitti David , Durocher Dan , Sicheri Frank , Al-awar Rima 
Published: August 2012

Abstract
Inositol-requiring enzyme 1 (IRE1) is a key player in endoplasmic reticulum (ER) stress conditions. IRE1 is a highly conserved ER-membrane protein activated by the unfolded protein response (UPR) or other ER-stressors, such as hypoxia and glucose deprivation. Stress causes IRE1 to undergo oligomerization and autophosphorylation, which triggers nonconventional splicing of XBP-1 mRNA by its cytosolic endonuclease domain. The resulting spliced XBP-1 protein (XBP-1s) is a transcription factor that serves to increase the protein folding capacity and ultimately restore homeostasis of the ER. Thus, sustained IRE1 activity promotes cell survival and inhibition of IRE1 may be a potential therapeutic target for diseases associated with chronic ER-stress, such as neurodegenerative disorders, diabetes, and cancer. Proper RNase function of IRE1 is dependent upon autophosphorylation of the kinase domain. We therefore screened a library of 380 known kinase inhibitors, consisting of tool compounds and compounds already in clinical use, for those with activity against the human IRE1 kinase domain. As a result, a number of compounds were found that potently inhibit phosphorylation of a biotin-STK peptide substrate in the presence of human IRE1 (IC50 &lt; 1 μM), as determined by HTRF (homogeneous time-resolved fluorescence). The lead compounds were then screened in cell-based assays. Several ATP-mimetic compounds with diverse chemotypes were found to inhibit expression of XBP-1s in human cancer cells under pharmacologically-induced acute ER-stress. Furthermore, transcriptional targets of XBP-1s and phosphorylation of IRE1 were also negatively affected by these compounds. Interestingly one compound in particular, a known ROCK1 (Rho-associated coiled-coil containing protein kinase 1) inhibitor (OICR000287A), was significantly more toxic to cells under acute ER-stress than to unstressed cells. This study suggests that development of ATP-competitive inhibitors of human IRE1 is a promising therapeutic strategy for ER-stress related diseases including myeloma, pancreatic and other secretory cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4989. doi:1538-7445.AM2012-4989
Abstract 5002: Comprehensive DNA methylation profiling of human hepatocellular carcinoma
Authors: Nishimura Takafumi , Nishida Naoshi 
Published: August 2012

Abstract
&lt;Background and aim&gt; Transcriptional inactivation of several tumor suppressor genes via epigenetic mechanism has been reported in many types of cancers, including hepatocellular carcinoma (HCC), and thus has been considered as critical events in multistage carcinogenesis. We conducted a comprehensive genome-wide analysis to elucidate distribution and characteristics of genes that subject to cancer-related DNA methylation in human HCC, especially on the context of development of methylation alteration in early stage of human hepatocarcinogenesis. &lt;Materials and methods&gt; With written informed consent, five well-differentiated HCC tissues and two corresponding matched non-cancerous liver tissues were obtained at the time of hepatectomy (2 tumors) or orthotopic living-donor liver transplantation (3 tumors and 2 non-tumors). After bisulfite modification, the converted DNA was subject to hybridization on Infinium Human Methylation BeadChip 450K (Illumina, Inc., San Diego, CA) that includes 485,764 cytosine positions of the human genome including gene promoters and repetitive DNA elements. The methylation level for each CpG dinucleotides was represented as a beta value according to the fluorescent intensity ratio. In order to identify alteration of methylation profile between well-differntiated HCC and non-tumor liver, difference of average beta values between tumor and non-tumor was calculated. &lt;Results&gt; Of 25,978 CpG loci that represent each gene, differences of average beta values of 24,805 loci (95.5%) were within 30%. These were considered as constitutively methylated or unmethylated. Tumor-specific demethylation was found at 589 loci representing 414 genes. Of these, 85.0% were located outside CpG islands, shore or shelf. Tumor-specific demethylation rarely occurred within CpG islands (3.4%). On the other hand, tumor-specific DNA methylation was found at 137 loci representing 108 genes. Of these, 65.7% were located within CpG islands. According to previously published information (Lee, TI. et. al. Cell 125:301-313, 2006), 39 genes (36%) out of these 108 genes with tumor-specific methylation have been reported to be occupied with polycomb group protein SUZ12 in embryonic stem cells. &lt;Conclusion&gt; Tumor-specific methylation occurring at CpG islands, especially of polycomb target genes, may contribute to hepatocarcinogenesis. This finding further suggests an importance of epigenetic mechanism on developing human HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5002. doi:1538-7445.AM2012-5002
Abstract 5011: Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia
Authors: Lendvai Agnes , Johannes Frank , Grimm Christina , Eijsink Jasper JH , Wardenaar Rene , Volders Haukeline H. , Klip Harry G. , Hollema Harry , Jansen Ritsert C. , Schuuring Ed , van der Zee Ate GJ , Wisman G. Bea A. 
Published: August 2012

Abstract
Introduction: Cervical cancer is the second most common cancer in women worldwide and development of cervical cancer goes through different well-defined premalignant stages. Epigenetic modifications, such as aberrant DNA promoter methylation is frequently observed in cervical cancer. Identification of hypermethylated regions that allow discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia or worse (CIN2+) by DNA methylation state may improve current population-based screening programs for cervical cancer. In this study, the DNA methylome of CIN3 lesions were characterized using genome-wide methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methods and results: Methyl-DNA ImmunoPrecipitation (MeDIP) assay combined with DNA microarray hybridization was used to compare DNA methylation patterns of epithelial cells derived from CIN3 lesions with normal cervical epithelium. In total, 80 hypermethylated differentially methylated regions (DMRs) were identified that significantly distinguished CIN3 lesions from normal cervice. Selected DMRs (n=9) were evaluated by methylation-specific PCR (MSP) on additional tissue specimens including normal cervix, CIN2/3 and cervical cancer samples and showed hypermethylation in up to 94.7% in CIN2/3 and 100% in cervical cancers. Quantitative MSP (QMSP) for two candidate biomarkers was applied to explore the test performance in a large series of cervical scrapings. Frequency and relative level of DNA methylation were significantly different between normal and cancer samples (p&lt;0.05). In cervical scrapings from patients referred with an abnormal Pap smear, frequency and relative level of DNA methylation were also related with increasing severity of the underlying CIN lesion (p&lt;0.01) In addition, ROC analysis showed that the methylation level was discriminative between low-grade CIN lesions and CIN2+ (p&lt;0.05). Conclusion: Our study demonstrates specific DNA methylation patterns in high-grade CIN lesions through the newly identified discriminative hypermethylated DMRs and represents candidate biomarkers for early detection of high-grade CIN. This study was supported by the Dutch Cancer Society (NKB) (project-number RUG 2004-3161) and by OncoMethylome Sciences S.A., Liège, Belgium. CG was funded by the German Ministry of Education and Research (BMBF) within the NGFN-PLUS project PKT-01GS08111.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5011. doi:1538-7445.AM2012-5011
Abstract 5016: Epigenetics in renal cell carcinoma
Authors: Ramakrishnan Swathi , Sotomayor Paula , Lehet Kristin , Pili Roberto 
Published: August 2012

Abstract
In 2011, an estimated 60,920 men and women will be diagnosed of which 13,120 will die of cancer of the kidney and renal pelvis. The current standard line of therapy includes surgery [partial or radical nephrectomy] or the use of molecular targeted agents such as antiangiogenic agents or immunotherapy. The common mutations found in renal cell carcinomas [RCC] are Von-Hippau Lindau [VHL] gene in clear cell RCC, c-met gene in papillary RCC type I, Fumarate hydratase [FH] gene in papillary type II or the Brit Hogg Dube’ [BHD] gene in chromophobe RCC. However there have been several studies indicating that some of the above genes like VHL can be silenced through promoter methylation as well. Hence, there has been an increasing focus on epigenetic modifications that can occur in RCCs, because of the possibility of reversing these epigenetic marks. There have been considerable reports on the use of agents such as histone deacetylase [HDAC] inhibitors or DNA methyl transferase inhibitors in different RCC cell lines or clinical trials. In this study, we looked at the HDAC expression and activity in matched tumor and non-tumor renal cell carcinoma tissue obtained from tissue procurement services at RPCI. Class I HDACs [HDAC 1, 2 and 3] and two members of class II HDACs [HDAC 4 and 5] are overexpressed in tumors compared to their non-tumor counterparts. In contrast, a class II member HDAC 6 level is lower in the tumor tissues relative to their non-tumor counterparts which corresponded to higher levels to acetylated α-tubulin in those tumors. However, these HDAC expression levels did not tend to have a correlation with grade or stage. We also established xenografts, that are implanted orthotopically and efforts are underway to obtain relatively faster growing tumors subcutaneously. Ongoing studies include defining the relation between expression and activity of HDACs in these tissues and the interaction and impact of other proteins with Class I and II HDACs [such as ER-α, Class III HDACs, VHL] in the context of common active pathways in tumors such as hypoxia [results of which will be available at the time of the meeting]. Further work also includes to look into other histone as well as DNA modifications, as well as enzymes that cause these modifications, in the matched tissues and to explore the potential use of histone or DNA modifying agents as part of RCC treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5016. doi:1538-7445.AM2012-5016
Abstract 5017: DNA methylation array screening in salivary gland adenoid cystic carcinoma
Authors: Shao Chunbo , Tan Marietta , Bishop Justin A. , Vikani Ami R. , Ha Patrick K. 
Published: August 2012

Abstract
Objective: DNA methylation alterations, with either gain or loss of CpG methylation in the promoter region, can alter the expression of tumor suppressor genes or oncogenes. This contributes to the tumorigenesis of human cancers, including salivary adenoid cystic carcinoma (ACC). In this study, we used a DNA methylation array (Illumina HumanMethylation27 BeadChip, San Diego, CA) to screen for novel oncogene and tumor suppressor gene (TSG) candidates under the control of promoter methylation in ACC. Methods: The Illumina HumanMethylation27 BeadChip Array was used to analyze the DNA methylation patterns of ∼14.000 genes at 27,578 CpG sites in 21 ACC and 13 normal salivary gland tissues. With our basic screening algorithm, we narrowed the list down to ∼100 tumor suppressor gene candidates (hypermethylated in tumor) and oncogene candidates (hypomethylated in tumor). Next, the differential methylation levels in the promoter region of candidates were validated by bisulfite genomic sequencing in four primary ACC and four normal salivary gland tissues. Candidate genes that showed differential methylation were then confirmed by analyzing gene re-expression in seven cell lines treated with 5-Aza deoxycytidine, a global demethylating agent. Furthermore, the expression levels of the candidate genes were examined by quantitative reverse transcription PCR (qRT-PCR) in a separate ACC cohort. Lastly, the DNA methylation levels of promising candidate genes were validated by quantitative methylation specific PCR (qMSP) in a larger ACC cohort. Results: With the methylation array, we initially identified 28 oncogene candidates which displayed relative hypomethylation and 64 TSG candidates that showed relative hypermethylation in ACC compared to normal tissues. After the above mentioned additional validation steps were performed, we settled on two promising candidates, PDE9A and TP53TG3, that were significantly hypomethylated and overexpressed in primary ACC tumors compared to normal salivary gland tissue. Furthermore, the expression of PDE9A and TP53TG3 demonstrated consistent upregulation after 5-aza-cytidine treatment of cancer cell lines, suggesting that promoter methylation does play in a role in controlling gene expression. Conclusions: The Illumina HumanMethylation27 BeadChip array is a reliable and efficient tool for analyzing global gene methylation. It is useful in screening for novel oncogene and TSG candidates controlled by promoter methylation in salivary gland ACC. PDE9A and TP53TG3 were identified as promising novel oncogene candidates in salivary gland ACC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5017. doi:1538-7445.AM2012-5017
Abstract 5019: Reprogramming the cancer epigenome by “metabolic transduction”
Authors: Byun Jung S. , Gardner Kevin 
Published: August 2012

Abstract
This study focuses on the key concept of “metabolic transduction” as an important general mediator of cellular reprogramming in epithelial cancers. As a result of multiple studies on epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition in diverse epithelial cancers, the role of developmental plasticity during epithelial differentiation has emerged as a new area of research. Recent data from our lab suggest that metabolites and intermediates in cellular metabolism can act as secondary messengers to dynamically change and globally reprogram epigenetic signatures during normal development, tissue repair, and cancer. We refer to this process as metabolic transduction. Central to this concept is the role played by the C-terminal binding proteins, CTBP1 and CTBP2. Dimeric combination of these factors act as metabolic sensors that function, in the presence of the high energy intermediate NADH, to target multiple classes of chromatin modifying factors, including histone deacetylase, histone methyl-transferases, histone demethylases, DNA methyl-transferases to specific locales throughout the genome. Therefore, CTBP has the potential to mediate widespread changes in the epigenetic landscape and influence broad programs of cellular behavior. Genome-wide profiling studies by ChIP-seq reveal that CTBP controls a network of genes linked to cellular events that influence cellular re-programing or “plasticity” including stem cell transcriptional programs, angiogenesis, and EMT. These studies combined with immuno-histochemical profiling of patient samples indicates that CTBP plays an important role in driving progression of more aggressive forms of breast cancer including Triple Negative Breast Cancer and the basal-like subtypes. Recent studies in our group suggest a role for CTBP in enabling plasticity of cellular fate in malignant cells. Breast cancer cell lines capable of spontaneous de-differentiation into side populations with tumor initiation cell characteristic, such as Sum149PT, are highly enriched in CTBP and are dominated by CTBP controlled pathways. This association has significance in diverse types of cancer, since other transformed cell lines capable of spontaneous de-differentiation into side population, including the endometrial carcinoma cell line HEC-1A, show similar enrichment and dependency on CTBP. These striking similarities suggest that CTBP may represent a driver of a tumor cell plasticity, implicating this tumor cell feature as a new hallmark of epithelial cancers. Therefore, strategies to target CTBP, and cellular reprogramming in general, may provide new opportunities for therapeutic intervention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5019. doi:1538-7445.AM2012-5019
Abstract 5021: Native accessible ChIP: A novel approach to interrogate protein-DNA interactions in accessible chromatin
Authors: Okino Steven T. , Meng Xiangdong , Kong Michelle , Wang Yan 
Published: August 2012

Abstract
Recently we developed novel technology for isolating accessible chromatin. When cells are permeabilized and treated with nuclease in situ, small DNA fragments, corresponding to accessible chromatin can be easily isolated and characterized. These DNA fragments, when analyzed by next-generation sequencing, provide a global map of accessible chromatin. We now report that the accessible chromatin isolated from cells is still associated with its cognate DNA-binding proteins and histones. Based on this, we developed a novel chromatin immunoprecipitation (ChIP) assay that does not require protein-DNA cross-linking or DNA shearing. Using this method, termed NA-ChIP (for native accessible ChIP), we demonstrate that RNA polymerase II (RNAPII), TBP and H3K4me3 are all associated with active promoters, but are rarely detected at silenced promoters. Comparison of NA-ChIP and a standard ChIP assay shows that immunoprecipitation (IP) efficiency is similar, but IP specificity is dramatically different. To measure IP specificity we compared the ratio of active promoter DNA precipitated with RNAPII (signal) relative to inactive promoter DNA precipitated (noise). We find that NA-ChIP is highly specific with a signal-to-noise ratio &gt;500; standard ChIP is less specific with a signal-to-noise ratio of about 9. We conclude that NA-ChIP offers significant advantages over standard ChIP, including dramatically reduced background and an easier workflow.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5021. doi:1538-7445.AM2012-5021