bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2397: Epigenetic silencing in clear renal cell carcinoma: KEAP1 promoter hypermethylation
Authors: Fabrizio Federico Pio , Costantini Manuela , Copetti Massimiliano , Torre Anna Maria la , Sparaneo Angelo , Fontana Andrea , Poeta Maria Luana , Gallucci Michele , Sentinelli Steno , Graziano Paolo , Parente Paola , Pompeo Vincenzo , Salvo Laura De , Simone Giuseppe , Papalia Rocco , Picardo Francesco , Balsamo Teresa , Flammia Gerardo Paolo , Trombetta Domenico , Pantalone Angela , Kok Klaas , Ferronika Paranita , Muscarella Lucia Anna , Fazio Vito Michele 
Published: July 2017

Abstract
The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defense genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma, but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete.
Here we performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 37 tumor/normal paired tissues of clear cell Renal Carcinoma (ccRCCs). Promoter methylation analysis was performed by using a quantitative methylation specific PCR assay in real time, whereas mutation scanning was performed on FFPE tissues by direct sanger sequencing of the exons 4-7 codifying for the DGR domain of the Keap1 protein.
A tumor-specific DNA methylation of the KEAP1 gene promoter region was found in 18 out of 37 ccRCCs (48,6%) and a direct effects on the modulation of Keap1 mRNA levels was confirmed by in vitro 5-azacytidine treatment on three different ccRCCs cell lines. Analysis of an independent TGCA data set corroborate the epigenetic findings and reveals a significant correlation in multivariate analysis of epigenetic KEAP1 silencing with Overall Survival in ccRCCs.
Our results further suggest that epigenetic deregulation of the Nrf2/Keap1 system could play a pivotal role in the cancerogenesis of ccRCCs. In addition identifying patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction and response to therapy in ccRCC affected patients.
Citation Format: Federico Pio Fabrizio, Manuela Costantini, Massimiliano Copetti, Anna Maria la Torre, Angelo Sparaneo, Andrea Fontana, Maria Luana Poeta, Michele Gallucci, Steno Sentinelli, Paolo Graziano, Paola Parente, Vincenzo Pompeo, Laura De Salvo, Giuseppe Simone, Rocco Papalia, Francesco Picardo, Teresa Balsamo, Gerardo Paolo Flammia, Domenico Trombetta, Angela Pantalone, Klaas Kok, Paranita Ferronika, Lucia Anna Muscarella, Vito Michele Fazio. Epigenetic silencing in clear renal cell carcinoma: KEAP1 promoter hypermethylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2017-2397
Abstract 2409: Loss of L1TD1 suppresses Notch1 induced LINE1 methylation and genomic stability
Authors: Chiu Chia-Chen , Huang Wei-Chen , Lee Kuan-Der , Chen Chih-Cheng , Hsu Chia-Chen , Kang Mei-Ling , Leu Yu-Wei , Hsiao Shu-Huei 
Published: July 2017

Abstract
The silencing of endogenous retrotransposon like LINE1 is critical for the maintenance of genomic stability and the LINE-1 type transposase domain containing 1 (L1TD1) gene possesses the repeated, putative LINE-1 RNA-binding domains and was hypothesized to regulate the activity of LINE-1 through DNA methylation. To verify if L1TD1 is responsible for LINE-1 silencing and the maintenance of somatic genome stability, CRSPR/Cas9 system was used to knockout (KO) L1TD1 locus in gastric, colon and breast cancer cells so as in the mesenchymal stem cells (MSCs). We observed that L1TD1 KO blocked the entrance of SUV39H1, histone methyl transferase, into cell nuclear which suppressed the tri-methylation of histone 3 at lysine 9 (H3k9me3) and LINE-1 methylation. A global demethylation and reduced HP1α recruitment were also observed. The global distribution of CTCF binding loci was also distorted as well as the bivalent histone marks. Further, L1TD1 KO distorted normal distribution of RassF1A expression, cytoskeleton conformation and therefore cell stiffness. The MSC-to-neuron differentiation was also blocked by the KO. Further, we found that overexpressed Notch-1 increased DNA methylation within LINE1 promoter, and this increase was attenuated by L1TD1 KO. Therefore, we conclude that the external signals like Notch1 affect L1NE1 methylation and genome stability through possible LINE1 interacting L1TD1. Since L1TD1 hypermethylation was observed in colon (n=100), gastric (n=19) and breast (n=79) cancers, L1TD1 abnormality is then a candidate for cancer biomarker. (Supported by: MOST-105-2320-B-194-004, MOST-105-2314-B-182A-134, MOST Taiwan and CMRPG6F0092, Chang Gung Memorial Hospital, Chia-Yi, Taiwan)
Citation Format: Chia-Chen Chiu, Wei-Chen Huang, Kuan-Der Lee, Chih-Cheng Chen, Chia-Chen Hsu, Mei-Ling Kang, Yu-Wei Leu, Shu-Huei Hsiao. Loss of L1TD1 suppresses Notch1 induced LINE1 methylation and genomic stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2409. doi:10.1158/1538-7445.AM2017-2409
Abstract 2412: Monitoring small molecules and macromolecules methyltransferase activities using homogenous luminescent assay
Authors: Goueli Said A. , Hsiao Kevin 
Published: July 2017

Abstract
It is well recognized that methylation/demethylation of not only DNA, RNA, Proteins but also methylation of small molecules play major roles in modulation of the epigenome, transcriptome, neurotransmitter uptake and metabolic regulation. Recent biochemicval and biological data suggest that the activity of these enzymes and their expression level are under very strict regulation and any abnormal alteration in either one or both results in a wide varieties of pathogenic conditions such as cancer, inflammation, and neurodegenerative diseases. In addition to chromatin modulation, altered methylation of DNA and more recently mRNA have been recognized to regulate the transcriptome and the rate of message translation and stability. Furthermore, methylation of small molecules such as catechols and nicotinamide play critical roles in neurotransmitters uptake and function, and metabolic regulation, respectively. Thus, pharmacological modulation of these enzymes by small molecules will be beneficial in developing novel therapeutics for multiple unmet medical needs. Towards this goal of searching for activators/inhibitors of these enzymes for the development of next generation of drugs, screening assays for these modulators are urgently needed. To address these unmet needs, we have developed a novel assay that monitors the activities of these enzymes and their modulation by small molecules. The assay is bioluminescent based, HTS formatted and highly sensitive. A unique feature of this assay is its universality since it is based on monitoring the formation of the universal product S-adenosylhomocysteine (SAH), i.e., capable of detecting changes in activity of a broad range of methyltransferases such as DNA, RNA, protein, and small molecules. In addition, the assay has been validated for all classes of protein methyltransferases (Lysine and Arginine), and with different types of substrates (small peptides, large proteins, or even nucleosomes). This enables determining the specificity of these enzymes and their substrate requirements. The assay has high signal to background, low C.V., robust (Z’ value &gt; 0.7), and has been validated using various plate densities such as 96-, 384, and 1536-well plates. A strong feature of this assay is its utility with broad range of substrates concentrations or the composition of the substrates (short vs. long peptides), thus enabling the generation of kinetic data and determining the mechanism of action of various modulators of methyltransferases of interest.
Citation Format: Said A. Goueli, Kevin Hsiao. Monitoring small molecules and macromolecules methyltransferase activities using homogenous luminescent assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2412. doi:10.1158/1538-7445.AM2017-2412
Abstract 2418: Characterization of the PAX8 regulatory network in epithelial ovarian cancer
Authors: Corona Rosario I. , Adler Emily , Lee Janet M. , Rodriguez-Malave Norma , Mhawech-Fauceglia Paulette , Sowter Heidi , Hazelett Dennis J. , Lawrenson Kate , Gather Simon A. 
Published: July 2017

Abstract
PAX8 is a lineage-restricted transcription factor expressed in a large proportion of epithelial ovarian cancers (EOCs). PAX8 is commonly upregulated in EOCs relative to precursor tissues, suggesting it functions as an oncogene. However, the biological role of PAX8 during cancer initiation and development is poorly understood, and the genome-wide transcriptional targets have yet to be comprehensively catalogued. Using stable models of PAX8 knockdown in HEYA8 and IGROV1 EOC cell lines we show that PAX8 knockdown reduces cell proliferation in vitro and tumor growth in vivo. To understand how PAX8 regulates neoplastic phenotypes in cancer cells we performed RNA expression profiling by microarray in HEYA8 and IGROV1 before and after PAX8 knockdown. We also performed chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) for PAX8 and a marker of active chromatin (H3K27ac) in both cell lines. De novo motif discovery in the ChIP-seq profiles identified a PAX-like binding motif and several potential PAX8 cofactors in IGROV1 that are not enriched in HEYA8. These cofactors include members of the TEAD and Sp/KLF families of transcription factors. We divided the genes from our differential expression (DE) analysis in PAX8 knockdown into three non-overlapping categories: (a) direct regulatory targets (RTs), i.e. DE genes with PAX8 binding sites in their promoter regions; (b) putative enhancer RTs, where DE genes and PAX8 binding sites reside within the same topological association domain (TAD) defined from embryonic stem cells; and (c) indirect RTs. Our findings reveal that PAX8 can function as either an activator or a repressor, and that PAX8 regulates a very different set of genes in each cell line, as only a small fraction RTs (~50) is shared between HEYA8 and IGROV1. Nonetheless, independent pathway enrichment analysis reveals four pathways downstream of PAX8 that are common to both cell lines: DNA replication, cellular response to lipopolysaccharides, TNFA signaling via NFKB and anatomical structure morphogenesis. Individually, we discovered enrichment for G2M checkpoint and EMT signaling in HEYA8, and tissue morphogenesis and mesenchymal cell development in IGROV1. Collectively, our results suggest that PAX8 regulates cell proliferation and cancer promoting processes via highly tissue-specific regulation of common oncogenic pathways.
Citation Format: Rosario I. Corona, Emily Adler, Janet M. Lee, Norma Rodriguez-Malave, Paulette Mhawech-Fauceglia, Heidi Sowter, Dennis J. Hazelett, Kate Lawrenson, Simon A. Gather. Characterization of the PAX8 regulatory network in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2418. doi:10.1158/1538-7445.AM2017-2418
Abstract 2421: The role of p53 mutational status and SOX9 suppression in chemotherapy response of ovarian cancer
Authors: Cutter Noelle L. , Lucito Matthew , Frank Ryan , Doyle Kimberly 
Published: July 2017

Abstract
Ovarian cancers are highly heterogeneous where platinum based chemotherapy which induces DNA crosslinking resulting in apoptosis of the cell is the preferred treatment. However, many patients are intrinsically resistant or quickly develop resistance. The Sox factors are a large family of transcription factors that play important roles in tumor development and progression in a variety of human malignancies and diverse developmental processes, but their impact in clinical tumorigenesis is still unclear. An analysis of genomic changes in ovarian cancer has provided the most comprehensive and integrated view of cancer genes for any cancer type to date. Ovarian serous adenocarcinoma tumors from 500 patients were examined by The Cancer Genome Atlas (TCGA) Research Network and analyses are reported in a recent issue of Nature. This evidence suggests that epigenetic deregulation, such as methylation, may be a key factor in the onset and maintenance of chemoresistance. Previous microarray analysis results in our lab correctly identified a subset of about 300 genes that when methylated altered the chemoresistance of the ovarian epithelium cells in culture. Of the genes identified in the analysis we further set out to characterize oncogenes and tumor suppressor genes that interact with the guardian of the genome, TP53, to determine if we could elucidate the mechanism by which it increased resistance. Using several in-vitro assays, we determined that the loss of p53 in conjunction with SOX9 decreased the level of apoptosis in response to carboplatin. Furthermore, in cells with mutated p53/SOX9 show an increase in tumorigenesis. Regulation of several pathways with p53 mutations in ovarian cancer might represent a therapy response prediction and could be a future therapeutic target for ovarian cancer. In addition, the crosstalk between p53/SOX9 and epigenetic regulators may present a valid treatment option for increasing carboplatin sensitivity in resistant patients.
Note: This abstract was not presented at the meeting.
Citation Format: Noelle L. Cutter, Matthew Lucito, Ryan Frank, Kimberly Doyle. The role of p53 mutational status and SOX9 suppression in chemotherapy response of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2421. doi:10.1158/1538-7445.AM2017-2421
Abstract 2423: Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents
Authors: Xiong Donghai , Pan Jing , Zhang Qi , Szabo Eva , Miller Mark S. , Lubet Ronald A. , You Ming , Wang Yian 
Published: July 2017

Abstract
Due to exposure to environmental toxicants, a “field cancerization” effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged epithelium of bronchial airways with dysregulated gene expression patterns. Using a mouse model of lung squamous cell carcinoma (SCC), we performed transcriptome sequencing (RNA-Seq) to profile bronchial airway gene expression and found activation of the PI3k and Myc signaling networks in cytologically normal bronchial airway epithelial cells of mice with preneopastic lung SCC lesions, which was reversed by treatment with the PI3K Inhibitor XL-147 and pioglitazone, respectively. Activated MYC signaling was also present in premalignant and tumor tissues from human lung SCC patients. In addition, we identified a key microRNA, mmu-miR-449c-5p, whose suppression significantly up-regulated Myc expression in the normal bronchial airway epithelial cells of mice with early stage SCC lesions. We developed a novel bronchial genomic classifier in mice and validated it in humans. In the classifier, Ppbp (pro-platelet basic protein) was overexpressed 115 fold in the bronchial airways of mice with preneoplastic lung SCC lesions. This is the first report that demonstrates Ppbp as a novel biomarker in the bronchial airway for lung cancer diagnosis.
Citation Format: Donghai Xiong, Jing Pan, Qi Zhang, Eva Szabo, Mark S. Miller, Ronald A. Lubet, Ming You, Yian Wang. Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2423. doi:10.1158/1538-7445.AM2017-2423
Abstract 2427: Alterations in gene expression after exposure of MDA-MB-231 cells to isobutylparaben
Authors: Strelchuk Christine , Taggart Holly Jones 
Published: July 2017

Abstract
Parabens are a group of chemical compounds extensively used as preservatives in consumer products such as cosmetics, pharmaceuticals and processed food. Parabens have been shown to have endocrine disrupting properties, to accumulate in breast tissue and to increase the proliferation of hormone receptor positive breast cancer cell lines through competitive binding to the estrogen receptor. Studies have shown that isobutylparaben has the highest binding affinity for the aryl hydrocarbon receptor (AhR), reported to bind environmental toxins. This study examined the alterations in gene expression correlated to exposure of the hormone receptor negative breast cancer cell line MDA-MB-231 to isobutylparaben over a 72 hour time frame. Exposure of the cells to concentrations of isobutylparabens commonly found in consumer products alters the genetic expression profile of the cells. In our study, detectable expression levels of AhR mRNA decreased, while cytochrome P450 (CYP1A1) and receptor activator of NFκB ligand (RANKL) mRNA levels increased, as analyzed by qPCR. The downregulation of AhR and altered expression levels of invasion related genes is suggestive of an increased metastatic phenotype with exposure to isobutylparaben.
Citation Format: Christine Strelchuk, Holly Jones Taggart. Alterations in gene expression after exposure of MDA-MB-231 cells to isobutylparaben [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2427. doi:10.1158/1538-7445.AM2017-2427
Abstract 2428: The cytidine deaminase APOBEC3B is a regulator of gene expression in breast cancer
Authors: Periyasamy Manikandan 
Published: July 2017

Abstract
The APOBEC3B (A3B) cytidine deaminase gene has been implicated driving the mutational landscape in breast and other cancer types. We have discovered that A3B is a co-activator of estrogen receptor (ER) mediated gene expression in breast cancer. Mechanistic studies established that A3B regulates gene expression by promoting C-to-U deamination at ER binding regions. We show that these C-to-U changes lead to the generation of DNA strand breaks through activation of base excision repair (BER) and to repair by non-homologous end-joining (NHEJ) pathways. We have performed RNA-seq and A3B ChIP-seq, in multiple ER+ and ER- breast cancer cell lines. Remarkably, these studies demonstrate that A3B regulates the expression of many genes in inflammatory and interferon signaling pathways, in addition to the regulation of ER target genes. These findings, together with other data to be presented, provide a clear role for A3B in transcription regulation. These findings also raise the possibility that transcription factor mediated recruitment of A3B to DNA may facilitate acquisition of A3B driven cancer mutations.
Citation Format: Manikandan Periyasamy. The cytidine deaminase APOBEC3B is a regulator of gene expression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2428. doi:10.1158/1538-7445.AM2017-2428
Abstract 2429: Generation of a transcriptome of oncogenic mutant p53 in triple-negative breast cancer
Authors: Steele Rebecca E. , McDade Simon S. , Mullan Paul B. 
Published: July 2017

Abstract
The purpose of this study was to generate a transcriptional profile specific for mutant p53 in triple-negative breast cancer (TNBC), representing potential novel therapeutic targets. The highly heterogeneous TNBC tumor subgroup is established as having a poor clinical outcome. There are currently no targeted therapies for women with TNBC; consequently, there is an unmet clinical need to identify targetable pathways. Approximately 75% of these tumors are known to harbour a mutation in Tp53 (mutp53). Chromatin Immunoprecipitation Sequencing (ChIP-Seq) for mutp53 and ETS-1 (a known mutp53 interactor) was carried out using the D0-1 (sc-126) and sc-20 antibodies respectively, in the MDA-MB-468 TNBC cell line. The aim of these ChIP-seq experiments was to identify sites bound by endogenous R273H mutp53 and ETS-1 and to confirm that target genes were co-regulated. We identified 282 novel mutp53 specific genomic binding sites and 37 mutant p53 and ETS1 shared binding sites. In-house data analysis and peak calling generated a list of potential transcriptionally co-regulated genes adjacent to these genomic sites. PDGFβ, TRIB3, BTRC, TNFSF18 & PI3 were successfully validated as being transcriptionally regulated by R273H mutp53 and not wild-type p53 (as shown by MCF7 ChIP-seq comparisons). A number of these genes are known to be aberrantly expressed in TNBC patient tumors and harbor interesting immune biology, providing potential opportunities for novel therapeutic strategies. In addition, DNA damaging chemotherapy-resistant MDA-MB-468 derivatives express elevated levels of mutp53 protein and altered expression of our validated transcriptional targets, suggesting that they may also have roles in promoting resistance to current chemotherapy treatments, downstream of mutp53. In conclusion, we have identified a cohort of ‘mutp53 specific’ transcriptional targets which may have roles in modulating immune responses to TNBCs, driving resistance to current chemotherapies and could provide opportunities for the development of novel treatments for TNBCs.
Citation Format: Rebecca E. Steele, Simon S. McDade, Paul B. Mullan. Generation of a transcriptome of oncogenic mutant p53 in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2429. doi:10.1158/1538-7445.AM2017-2429